Download Report on Human Embryonic Stem Cell Research

COMMISSION OF THE EUROPEAN COMMUNITIES
Brussels, 3.4.2003
SEC(2003) 441
COMMISSION STAFF WORKING PAPER
REPORT ON HUMAN EMBRYONIC STEM CELL RESEARCH
TABLE OF CONTENTS
Executive summary…………………………………………………………………...4
1.
Introduction…………….……………………………………………………………15
Chapter 1: Origin and characteristics of human stem cells and potential application
for stem cell research.............................................................................................. 17
1.1.
Origin and characteristics of human stem cells ....................................................... 17
1.2.
Plasticity of human somatic stem cells.................................................................... 19
1.3.
Potential application of human stem cell research................................................... 20
1.4.
Novel stem cell based therapies .............................................................................. 22
1.5.
Scientific and technical obstacles to overcome before realising the potential clinical
uses of novel human stem cell based therapy .......................................................... 22
1.6.
Examples of novel stem cell based therapies, which are currently subject to extensive
research.................................................................................................................. 23
2.
Chapter 2: Human embryonic stem cell research .................................................... 26
2.1.
Origin and characteristics of human embryonic stem cells ...................................... 26
2.2.
Possible sources for human embryonic stem cells ................................................... 26
2.3.
Growing human embryonic stem cells in the laboratory.......................................... 27
2.4.
The current advantages and limitations of human embryonic stem cells and human
somatic stem cells................................................................................................... 28
2.5.
Examining the need for new human embryonic stem cell lines. .............................. 30
2.6.
Developments regarding establishment of human stem cell banks and registries..... 31
3.
Chapter 3: Governance of human embryonic stem cell research.............................. 34
3.1.
The ethical issues at stake....................................................................................... 34
3.2.
Regulations in EU Member States regarding human embryonic stem cell research. 38
3.3.
New regulations under discussion in EU Member States ........................................ 44
3.4.
Regulations in some non-EU countries regarding human embryonic stem cell
research.................................................................................................................. 46
3.5.
Governance of stem cell research in the context of FP6 .......................................... 48
3.6.
Social scrutiny and dialogue ................................................................................... 51
4.
Chapter 4: Socio-economic aspects ........................................................................ 53
GLOSSARY ........................................................................................................................ 56
ANNEX A: Biology of human development ........................................................................ 60
ANNEX B: Possibilities to overcome immune rejection responses in stem cell therapy........ 62
2
ANNEX C: Examples of available human embryonic stem cell lines ................................... 64
ANNEX D: Details regarding provisions in non-EU countries relating to human embryonic
stem cell research ................................................................................................... 66
ANNEX E: Opinion No.15 of the European Group on Ethics regarding ethical aspects of
human stem cell research and use E - Opinion EGE ............................................... 70
ANNEX F: Statement for the minutes of the Council meeting 30 September 2002............... 84
3
EXECUTIVE SUMMARY
Background:
Stem cell research is one of the promising areas of biotechnology, which offers the prospect
of developing new methods to repair or replace tissues or cells damaged by injuries or
diseases and to treat serious chronic diseases, such as diabetes, Parkinson’s, chronic heart
failure as well as stroke and spinal cord injuries. Stem cell research is expected to be equally
important for basic science to understand cell differentiation and growth as well as for other
specific medical applications such as for the understanding of disease development and for the
development of safer and more effective drugs. Scientists are intensively studying the
fundamental properties of stem cells.
One of the possible sources for stem cells is human pre-implantation embryos. However,
when this research involves the use of human embryos it raises the question of ethical values
at stake and of the limits and conditions for such research.
The complexity of this issue with its ethical implications has been highlighted in the process
of adoption of the Sixth Framework Programme for Research (FP6) and its implementing
Specific Programmes, where the specific issue of human embryonic stem cell research was
subject to debate.
In the 6th Framework Programme, Community stem cell research funding is foreseen under
Priority 1 « Life Sciences, Genomics and Biotechnology for human health », section i
“Application of knowledge and technologies in the fields of genomics and biotechnology for
health”. In particular, “research will focus on…development and testing of new preventive
and therapeutic tools, such as somatic gene and cell therapies (in particular stem cell
therapies)” 1.
Pending the establishment of detailed implementing provisions by end 2003 at the latest, the
Commission agreed however not to fund during this period research projects involving the
use of human embryos and human embryonic stem cells with the exception of projects
involving banked or isolated human embryonic stem cells in culture. The Commission stated
its intention of presenting to Council and European Parliament a report on human embryonic
stem cells, which would form the basis for discussion at an inter-institutional seminar on
bioethics2.
The present report is the result of this commitment, and aims to provide a description of the
state of play of the scientific, ethical, legal, social and economic issues related to human stem
cell research and human embryonic stem cell research.
1
2
OJ L 294 of 29.10.2002, p. 10.
See annex F.
4
The purpose of the report is to provide a basis for an open and informed debate at the abovementioned inter-institutional seminar3.
Taking into account the seminar’s outcome, the Commission will submit a proposal
establishing further guidelines on principles for deciding on the Community funding of
research projects involving the use of human embryos and human embryonic stem cells.
The content of the report
Characteristics of human stem cells
Stem cells have three characteristics that distinguish them from other types of cells:
–
they are non-differentiated (unspecialised) cells,
–
they can divide and multiply in their undifferentiated state for a long period.
–
under certain physiological or experimental conditions, they can also give rise to more
specialised differentiated cells such as nerve cells, muscle cells or insulin producing
cells etc.
Stem cells are found in the early embryo, in the foetus and the umbilical cord blood, and in
many tissues of the body after birth and in the adult. These stem cells are the source for
tissues and organs of the foetus and for growth and repair in the new born and adult body. As
development proceeds beyond the blastocyst stage (5-7 days after fertilisation), the proportion
of stem cells decrease in the various tissues and their ability to differentiate into different cell
types also decrease at least when they are situated in their natural environment.
Classification of human stem cells
In this report a distinction is made between three groups of stem cells, referring to their origin
and method of derivation:
1. Human embryonic stem cells, which can be derived from a preimplantation embryo at the
blastocyst stage.
2. Human embryonic germ cells, which can be isolated from the primordial germ cells of the
foetus.
3. Human somatic stem cells, which can be isolated from adult or foetal tissues or organs or
from umbilical cord blood.
Potential application of human stem cell research
Transplantation of haematopoïetic stem cells (from bone marrow, peripheral blood or
umbilical cord blood of a healthy donor) has been used for more than a decade to treat e.g.
haematological malignancies such as leukemia or congenital immuno-deficiencies.
3
Scientific terms are explained in the glossary.
5
Autologous transplantation (transplantation of stem cells from the patient’s own bone marrow
or peripheral blood) was introduced to rescue the bone marrow of patients who had received
high dose of chemotherapy. It is now increasingly being used as primary treatment of other
types of cancer such as breast cancer and neuroblastoma. Autologous stem cell transplantation
is also used experimentally to treat difficult auto-immune conditions and as a vehicle for gene
therapy. Today, over 350 centres in Europe are performing more than 18 000 bone marrow
transplants a year 4.
Novel stem cell based therapies (often called regenerative medicine or cell based therapies)
are also being investigated to develop new methods to repair or replace tissues or cells damaged
by injuries or diseases and to treat serious chronic diseases, such as diabetes, Parkinson’s,
chronic heart failure or stroke and spinal cord injuries. Stem cell research is expected to be
equally important for basic science as well as for other specific medical applications.
–
For the development of novel stem cell based therapies. Three therapeutic concepts
are currently being envisaged:
–
Transplantation of differentiated cells derived from stem cells: Stem cells
may be grown and directed to differentiate into specific cell types in the
laboratory and then be transplanted (e.g. insulin producing cells to treat
diabetes, heart muscle cells to treat heart failure or dopamine producing
neurones to treat Parkinson’s disease etc...) The source for the specific
differentiated cell types could be embryonic or somatic stem cells, including
the patient’s own stem cells.
–
Direct administration of stem cells: In some cases it may be possible and/or
necessary to administer stem cells directly to the patient in such a way that they
would colonise the correct site of the body and continuously differentiate into
the desired cell type (e.g. systemic “Homing”).
–
Stimulation of endogenous stem cells: The possibility that self-repair could be
induced or augmented by stimulating an individual’s own population of stem
cells for example by administrating growth factors is also being explored.
These novel stem cell based therapies are still at their very early stage of
development. In particular regarding the transplantation of differentiated cells
derived from stem cells, several scientific and technical hurdles needs to be resolved
before clinical application of these therapies, including
4
–
Understanding of the mechanisms regulating stem cell growth, fate,
differentiation and dedifferentiation.
–
Eliminating the risk of development of inappropriate differentiated cells and
cancerous cells. The risk of tumorigenicity has in particular been highlighted
concerning the use of human ES cells as these stem cells develop teratomas.
–
Ensuring the function and viability of the stem cells or their derivatives during
the recipient’s life.
A. L. Lennard and G H Jackson, “Science, medicine and the future: Stem cell transplantation”, BMJ,
2000, 321: 433-437.
6
–
Overcoming the problem of immune rejection (which does not arise in the case
where the patient’s own stem cells can be used).
–
For the generation of human cells lines to be used in drug development at preclinical stage and in toxicology. Normal human cell types generated from human
stem cells can be genetically or pharmacologically manipulated and used for drug
discovery. These cell lines may provide more clinically relevant biological systems
than animal models for drug testing and are therefore expected to contribute to the
development of safer and more effective drugs for human diseases and ultimately to
reduce the use of animals. They also offer the possibility to develop better in vitro
models to enhance the hazard identification of chemicals. It is possible that these
applications will turn out to be the major medical impact of human ES cell research
at least in a short-term perspective, as the problems of immune rejection, viability
and tumorigenicity do not apply here.
–
For the understanding of human development. Human ES cells should offer
insights into developmental events that cannot be studied directly in the intact human
embryo but that have important consequences in clinical areas, including birth
defects, infertility, and pregnancy loss.
–
For the understanding of the basic mechanisms of cell differentiation and
proliferation. The understanding of the genes and molecules, such as growth factors
and nutrients, that function during development of the embryo may be used to grow
stem cells in the laboratory and direct their development into specialized cell types.
Some of the most serious medical conditions, such as cancer, are due to abnormal
cell division and differentiation. A better understanding of the genetic and molecular
controls of these processes may yield information about how such diseases arise and
suggest new strategies for therapies.
The current advantages and limitations of human embryonic and somatic stem cells and
the needs regarding the derivation of new human embryonic stem cell lines
In light of the current state of knowledge, human embryonic and somatic stem cells each have
advantages and limitations regarding their potential uses for basic research and novel stem
cell based therapies.
It is a matter of debate within the scientific community whether human embryonic stem cells
have a greater potential than human somatic stem cells (isolated from foetal or adult tissue).
Currently, human ES cells are of particular interest because they have the potential to
differentiate into all cell types in the body (they are pluripotent). The recent reports5
indicating that somatic stem cells may have a greater potential for differentiation into different
cell types than previously thought (for example bone marrow stem cells under certain
experimental conditions may differentiate into neurones, skeletal and cardiac muscle cells),
have opened up the question whether research on human embryonic stem cell is needed and
ultimately whether the derivation of new human embryonic stem cell lines may be obsolete at
this stage. In spite of the optimism generated by the recent research reports on the
pluripotentiality of human somatic stem cells, many scientists, including those who conduct
5
e.g. Jiang, Yuehua et al., “Pluripotency of mesenchymal stem cells derived from adult marrow”, Nature,
2002, 418:41-49.
7
somatic stem cell research, support the continuation of human embryonic stem cell research,
and do not support the limitation of research to somatic stem cell research only6.
The conclusions of many reports7 have highlighted that it is too early to know what important
findings will come from embryonic or somatic stem cell research and which stem cells will
best meet the needs of basic research and clinical applications.
Several arguments have been put forward regarding the needs for derivation of new human
embryonic stem cell lines.
In particular that human embryonic stem cell research has only just begun and scientists do
not yet know if they have developed the best procedures for isolating or maintaining human
ES cells in culture. It has also been reported that many of the existing embryonic stem cell
lines have been patented in the US. This could create a position of dependence from private
industry in other parts of the world 8.
Governance of human stem cell research
Human embryonic stem cell research raises complex ethical questions. The question whether
it is ethically defensible to do research on embryonic stem cells can be described as a conflict
between different values, between different actors’ rights and obligations, or between the
short- and long-term interests of different groups. On the one hand, there is interest in new
knowledge that can lead to treatment of hitherto incurable diseases. On the other hand, when
this research involves the use of human embryos, it raises the question of ethical values at
stake and of the limits and conditions for such research9. Opinions on the legitimacy of
experiments using human embryos are divided according to the different ethical,
philosophical, and religious traditions in which they are rooted. EU Member States have taken
very different positions regarding the regulation of human embryonic stem cell research. It
confirms that different views exist throughout the European Union concerning what is and
what is not ethically defensible.
6
7
8
9
e.g. Dr. Catherine Verfaillie, University of Minnesota Medical School, stated during her presentation at
the US President’s Council on Bioethics meeting on 25 April 2002, http://www.bioethics.gov/
“Embryonic stem cells in humans are very much in their infancy, the same as we are for adult stem cell
biology, too, and so I don’t think we are anywhere close to be able to come up with new therapies at
this point in time. I would also like to reiterate that even though my laboratory and our group works on
adult stem cells, we have actually actively pursued investigators in embryonic stem cell research,
human embryonic stem cells, just so that within the same institution we would have laboratories that
have one cell, and other laboratories that have the other cell, so we would be in a position to compare
and contrast the potential of the different cell populations, and I think that it is very important”.
“Stem Cells: scientific progress and future research directions”, National Institute of Health (NIH),
Bethesda, USA, June 2001; Swiss National Advisory Commission on Biomedical Ethics: opinion on
human embryonic stem cell research, June 2002; The Health Council of the Netherlands’ report on
“Stem cells for tissue repair. Research on therapy using somatic and embryonic stem cells”, June 2002.
http://www.gr.nl/pdf.php?ID=429 ; House of Lords Select Committee UK, “Report on Stem cell
research”, February 2002; http:/:www.parliament.the-stationery-office.co.uk/pa/ld200102/ldselect/
ldstem/83/8301.htm; Swedish National Council of Medical Ethics: statement of opinion on embryonic
stem cell research, 17.01.2002, http://www.smer.gov.se/.
The Health Council of the Netherlands’ report on “Stem cells for tissue repair. Research on therapy
using somatic and embryonic stem cells”, June 2002. http://www.gr.nl/pdf.php?ID=429.
Annex E - Opinion No. 15 of the European Group on Ethics regarding the “Ethical aspects of human
stem cell research and use”. http://europa.eu.int/comm/european_group_ethics/index_en.htm.
8
Ethical issues at stake:
As highlighted in the opinion n° 15 of The European Group on Ethics in Sciences and New
Technologies regarding « Ethical aspects of human stem cell research and use”, issued 14
November 2000, 10 the following fundamental ethical principles are applicable to human
embryonic stem cell research:
–
The principle of respect for human dignity.
–
The principle of individual autonomy (entailing the giving of informed consent, and
respect for privacy and confidentiality of personal data).
–
The principle of justice and of beneficence (namely with regard to the improvement
and protection of health).
–
The principle of freedom of research (which is to be balanced against other
fundamental principles).
–
The principle of proportionality (including that research methods are necessary to the
aims pursued and that no alternative more acceptable methods are available).
In addition, the EGE considers it important to take into account, based on a precautionary
approach, the potential long-term consequences of stem cell research and use for individuals
and the society.”
Concerning the creation of embryos for research purpose the EGE considered that “the
creation of embryos for the sole purpose of research raises serious concerns since it
represents a further step in the instrumentalisation of human life” and deemed “ the creation
of embryos with gametes donated for the purpose of stem cell procurement ethically
unacceptable, when spare embryos represent a ready alternative source”.
Furthermore the EGE considered “that, at present, the creation of embryos by somatic cell
nuclear transfer for research on stem cell therapy would be premature, since there is a wide
field of research to be carried out with alternative sources of human stem cells (from spare
embryos, foetal tissues and adult stem cells”.
Concerning the ethical acceptability of human embryonic stem cell research in the context of
the Community Framework Programme, the EGE concluded that «//… there is no argument
for excluding funding of this kind of research from the Framework Programme of research of
the European Union if it complies with ethical and legal requirements as defined in this
programme”.
Secondly the EGE stated, that:
“Stem cell research based on alternative sources (spare embryos, foetal tissues and adult
stem cells) requires a specific Community research budget. In particular, EU funding should
be devoted to testing the validity of recent discoveries about the potential of differentiation of
adult stem cells. The EU should insist that the results of such research be widely disseminated
and not hidden for reasons of commercial interest.”
10
Annex E - Opinion No. 15 of the European Group on Ethics regarding the “Ethical aspects of human
stem cell research and use”. http://europa.eu.int/comm/european_group_ethics/index_en.htm.
9
The EGE identified the following principal requirements regarding human embryonic stem
cell research and the procurement of embryonic stem cells from supernumerary embryos:
–
Free and informed consent from the donating couple or woman.
–
Approval of the research by an authority.
–
No financial gain for donors.
–
Anonymity of the donors and protection of the confidentiality of personal information
of the donors.
–
Transparency regarding research results.
Concerning clinical research the EGE stressed the importance of:
–
Free and informed consent of the patient.
–
Risk-benefit assessment.
–
Protection of the health of persons involved in clinical trials.
Regulation of human embryonic stem cell research in EU Member States11
EU Member States have taken different positions regarding the regulation of human
embryonic stem cell research and new laws or regulations are being drafted or debated.
Taking into account the situation, as of March 2003, the following distinctions can be made:
–
Allowing for the procurement of human embryonic stem cells from
supernumerary embryos by law under certain conditions: Finland, Greece, the
Netherlands, Sweden and the United Kingdom.
–
Prohibiting the procurement of human ES cells from supernumerary embryos
but allowing by law for the import and use of human embryonic stem cell lines
under certain conditions: Germany. The import and use of human ES cell lines is
not explicitly prohibited in e.g. Austria, Denmark and France and authorisation is
still being discussed.
–
Prohibiting the procurement of human ES cells from supernumerary embryos:
Austria, Denmark, France, Ireland and Spain. The legislation in Spain only allows
the procurement of human ES cell from non-viable human embryos under certain
conditions.
–
No specific legislation regarding human embryo research or human ES cell
research: Belgium, Italy, Luxembourg and Portugal.
11
European Commission, DG Research, Directorate E: Survey on opinions from National Ethics
Committees or similar bodies, public debate and national legislation in relation to human embryonic
stem cell research and use (last update March 2003). “Survey on the National Regulations in the
European Union regarding Research on Human Embryos - B. Gratton - published by the Secretariat of
the EGE - European Commission - July 2002”.
10
–
Allowing by law for the creation of human embryos for research purposes: UK is
for the moment the only Member State, which allows by law for the creation of
human embryos either by fertilisation of an egg by a sperm, or by somatic cell
nuclear transfer (SCNT, also called therapeutic cloning) for stem cell procurement.
The bill under discussion in the Belgian Parliament would allow for the creation of
human embryos for research purposes including by SCNT. The Dutch Embryo Act
of 2002 includes a five-year moratorium for the creation of embryos for research
purposes including by SCNT.
–
Prohibiting the creation of human embryos for research purposes and for the
procurement of stem cells by law or by ratification of the Convention of the
Council of Europe on Human rights and Biomedicine signed in Oviedo on 4
April 1997: Austria, Denmark, Finland, France, Germany, Greece, Ireland,
Netherlands, Portugal and Spain.
New regulations under discussion in EU Member States:
Belgium: A bill on research on human embryos in vitro was approved by the Belgian Senate
in 2002 and it is now under discussion in the Parliament. The draft legislation proposes to
authorise the procurement of embryonic stem cells from supernumerary embryos under
certain conditions, and to create a “Federal Commission for scientific medical research on
embryos in vitro”.
Denmark: A revision of the current legislation to allow for the procurement of human ES
cells from supernumerary embryos is under discussion.
France: A revision of the Bioethics Law of 1994 has been approved by the Senate in January
2003 and should be discussed by the Parliament in the first semester of 2003. It proposes to
allow research on supernumerary human embryos including the procurement of human ES
cells for 5 years under certain conditions. A central authorizing body will be created.
Italy: a law on in vitro fertilisation is under discussion.
Portugal: A committee has been established in Portugal for the preparation of a law on
human embryo and human ES cell research.
Spain: A revision of the current legislation is under discussion.
In 1998 the National Committee for Human Artificial Reproduction was created. In its second
opinion, delivered in 2002, it advised to conduct human embryonic stem cell research using as
a source supernumerary embryos, estimated in Spain to be over 30 000.
The Ethics Advisory Committee for Scientific and Technological Research was established in
April 2002 and gave in February 2003 its first opinion on research on stem cells. It
recommended to the government that research on both adult and embryonic stem cells should
be implemented; that the legislation should be modified to allow the isolation of human
embryonic stem cells from supernumerary embryos.
Sweden: A revision of the current legislation is under discussion. The Parliamentary
Committee on Genetic Integrity proposed, in their report published 29 January 2003, not to
implement a general prohibition against producing fertilised eggs for research purposes. It
11
should also be noted, however, that in the view of the Committee the creation of embryos by
transfer of somatic cell nuclei (so called therapeutic cloning) should be treated in the same
way and thus in principle be allowed.
Regulations in countries acceding to the EU
Cyprus, Czech Republic, Estonia, Hungary, Lithuania, Slovak Republic, Slovenia have
ratified the Convention of the Council of Europe on biomedicine and human rights.
Concerning the countries acceding to the EU, no specific regulations regarding human
embryonic stem cell research have at present been implemented. Estonia, Hungary, Latvia,
Slovenia have implemented legislation authorising research on human embryos under certain
conditions. In Lithuania, Poland and the Slovak Republic human embryo research is
prohibited. No specific regulation regarding embryo research exist in Cyprus, Malta and the
Czech Republic. A bill is under preparation in Czech Republic.
Governance of stem cell research in the context of FP6
As stated in the Treaty of the European Union, article 6:
“1. The Union is founded on the principles of liberty, democracy, respect for human rights
and fundamental freedom, and the rule of law, principles which are common to the Member
States.
2. The Union shall respect fundamental rights, as guaranteed by the European Convention for
the protection of Human Rights and Fundamental Freedoms signed in Rome on 4 November
1950 and as they result from the constitutional traditions common to the Member States, as
general principles of Community law.
3. The Union shall respect the national identities of its Member States.
4. The Union shall provide itself with the means necessary to attain its objectives and carry
through its policies.”
In accordance with the EU Treaty, each Member State retains its full prerogative to legislate
on ethical matters. At the level of the Community, ethical principles have been defined with
regard to the funding of research under the research Framework Programme.
As far as FP6 is concerned, the following ethical principles have been established12:
–
“Fundamental ethical principles are to be respected. These include the principles
reflected in the Charter of fundamental rights of the EU including the protection of
human dignity and human life…”
–
“… in accordance with Community law”
–
“…in accordance with legislation, regulations and ethical guidelines in countries
where the research will be carried out.”
12
OJ L 232 of 29.8.2002, p.4; OJ L 294 of 29.10.2002, p. 8.
12
–
“The following fields of research shall not be financed under this programme:
–
research activities aiming at human cloning for reproductive purposes
–
research activity intended to modify the genetic heritage of human beings
which could make such change heritable 13
–
research activities intended to create human embryos solely for the purpose of
research or for the purpose of stem cell procurement, including by means of
somatic cell nuclear transfer (often referred to as therapeutic cloning).
–
… funding of research activities that are prohibited in all the Member States is in all
circumstances excluded.”
–
“In compliance with the principle of subsidiarity and the diversity of approaches
existing in Europe, participants in research projects must conform to current
legislation, regulations and ethical rules in the countries where the research will be
carried out.
–
In any case, national provisions apply and no research forbidden in any given
Member State will be supported by Community funding in that Member State.
–
Where appropriate, participants in research projects must seek the approval of
relevant national or local ethics committees prior to the start of the RTD activities.
An ethical review will be implemented systematically by the Commission for
proposals dealing with ethically sensitive issues, in particular proposals involving
the use of human embryos and human embryonic stem cells”.
–
As stated in the Council minutes of 30 September 200214 “The Council and the
Commission agree that detailed implementing provisions concerning research
activities involving the use of human embryos and human embryonic stem
cells…shall be established by 31 December 2003. The Commission will during that
period…not propose to fund such research, with the exception of banked or isolated
human embryonic stem cells in culture”.
Socio-economic aspects
While many of the demonstrations of the potential of stem cell research have arisen from
academia, the development of this potential i.e. into therapeutic products requires industrial
and commercial inputs. For example, industrial involvement will be needed for large scale
and good manufacturing production of cell lines, to support multicentre clinical trials,
marketing, distribution etc.
In 2001 about 30 public and private biotechnology firms were doing stem cell research and
about a dozen are currently investigating the potential of both somatic and embryonic stem
cells. Few, if any, companies are investing solely in human embryonic stem cell research.
13
14
Research relating to cancer treatment of the gonads can be financed.
Annex F.
13
Although considerable sums are available for investment in stem cell research, commercial
returns on such investments are for the moment modest. This reflects the fact that most of this
work is still at the basic research stage. Thus commercial interests are trying to position
themselves for major profits in the future, but still face uncertain research prospects,
therapeutic possibilities and the development of a regulatory environment, the latter largely
influenced by ethical issues and public concerns.
14
INTRODUCTION
This report, prepared by the Commission services, aims to provide an overview of:
–
Origin and characteristics of human stem cells and the potential application of stem
cell research.
–
Human embryonic stem cell research (somatic stem cell research will be addressed so
far as it is relevant to the discussion on human embryonic stem cell research).
–
Governance of human embryonic stem cell research including the ethical issues at
stake, regulations in the EU Member States, governance of stem cell research in the
context of FP6 and social scrutiny and dialogue.
–
Socio-economic aspects of human embryonic stem cell research and use.
The report is complemented by a series of annexes, as follows:
A. Biology of human development
B. Possibilities to overcome immune rejection responses in stem cell therapy
C. Examples of available human embryonic stem cell lines
D. Details regarding provisions in non-EU countries relating to human embryonic stem cell
research
E. Opinion n° 15 of the European Group on Ethics regarding “Ethical aspects of human stem
cell research and use” issued 14 November 2002.
F. Statement for the minutes of the Council meeting 30 September 2002
The report takes into account:
–
Information collected from the survey on opinions from National Ethics Committees
or similar bodies, public debate and national legislation in relation to human
embryonic stem cell research and use in EU Member States and non-EU countries.
The survey was conducted by the European Commission, DG Research, Directorate
E (last update March 2003);
–
Opinions and reports from the European Group on Ethics in Science and New
Technologies to the European Commission http://europa.eu.int/comm/european
_group_ethics/index_en.htm
–
Report and proceedings from the conference on “Stem cells: Therapies for the future?”
organised by the European Commission, DG Research under the aegis of the
European Group on Life Sciences; December 2001 http://europa.eu.int/comm/
research/quality-of-life/stemcells.html
15
–
Candidate Countries legislation related to ethical issues in science and research
Proceedings of the workshop of 8-10 December 2002 - Brussels - organised by the
European Commission - DG Research – Directorate C
–
U. S. National Institutes of Health (NIH) documents regarding stem cells
http://nih.gov/news/stemcell/
–
Review of recent literature;
–
Presentations and communications from the scientific community.
16
Chapter 1: Origin and characteristics of human stem cells and
potential application for stem cell research
1.
CHAPTER 1: ORIGIN
1.1.
Origin and characteristics of human stem cells 15
AND CHARACTERISTICS OF HUMAN STEM CELLS AND
POTENTIAL APPLICATION FOR STEM CELL RESEARCH
Stem cells differ from other kind of cells in the body by their unique properties of: 1) being
capable of dividing and renewing themselves for long periods, 2) being unspecialised and 3)
being able to give rise to specialised cell types. They are found in the early embryo, in the
foetus and the umbilical cord blood, and in some (possibly many) tissues of the body after
birth and in the adult. These stem cells are the source for tissues and organs of the foetus and
for growth and repair in the newborn and adult body. As development proceeds beyond the
blastocyst stage (5-7 days after fertilisation), the proportion of stem cells decrease in the
various tissues and their ability to differentiate into different cell types also decrease at least
when they are situated in their natural environment. (See also chapter 1.2.).
Figure 1
spermatozoid
ORIGIN AND
CLASSIFICATION OF
STEM CELLS
oocyte
Fertilisation
day 0
Day 4-5
Morula
Morula
Embryonic stem cells
Day 5-7
Human embryonic germ cells
(from the primordial germ cells of the foetus)
From 8th
week after
fertilisation
+ umbilical
cord blood
Somatic stem cells
Adult
15
The Health Council of the Netherlands’ report on “Stem cells for tissue repair. Research on therapy using
somatic and embryonic stem cells”, June 2002. http://www.gr.nl/pdf.php?ID=429; US NIH, “Stem Cells:
A primer” September 2002 http://www.nih.gov/news/stemcell/primer.htm.
17
Classification of human stem cells:
The classification of stem cells is still subject to discussion and the use of different
definitions, both in the scientific literature and in public debates, often creates confusion. In
this report a distinction is made between three groups of stem cells, referring to their origin
and method of derivation16:
1. Human embryonic stem cells
Human embryonic stem cells derived from preimplantation embryo at the blastocyst stage
(see chapter 2 for further details)
2. Human embryonic germ cells
Stem cells with embryonic characteristics have also been isolated from the primordial germ
cells of the 5-10 weeks foetus. It is from these embryonic germ cells that the gametes (ova or
sperm) normally develop. Research has shown that germ cell derived stem cells have the
ability to differentiate into various cell types, although they are more limited in this respect
than embryonic stem cells17. It should be noted that these research results have yet to be
confirmed by other scientists and that the stability of these cells’ genetic material is still open
to discussion.
3. Human somatic stem cells
A somatic stem cell is an undifferentiated cell found among differentiated cells in a tissue or
organ, which can renew itself and can differentiate to yield the major specialised cell types of
the tissue or organ. Although somatic stem cells are rare, many, if not most, tissues in the
foetus and human body contain stem cells, which, in their normal location, have the potential
to differentiate into a limited number of specific cell types in order to regenerate the tissue in
which they normally reside. These stem cells, defined as somatic stem cells, are usually
described as “multipotent”. Scientists have found evidence for somatic stem cells in many
more tissues than they once thought possible. Examples of the tissues reported to contain stem
cells include liver, pancreas, brain, bone marrow, muscle, olfactory epithelium, fat and skin 18.
Some stem cells remain very active during postnatal life (e.g. haematopoïetic stem cells, skin
and gut stem cells), others seem relatively inactive (e.g. stem cells in the brain). It should be
mentioned that recent published data have suggested that, for example cells in the liver and
even the adult human brain may respond to injury by attempting repopulation19.
Possible sources for human somatic stem cells:
–
Adult tissues and organs: Somatic stem cells can be obtained by means of invasive
intervention, such as that used in connection with donation of bone marrow.
Haematopoïetic stem cells are routinely collected through the peripheral blood. It has
16
The Health Council of the Netherlands’ report on “Stem cells for tissue repair. Research on therapy
using somatic and embryonic stem cells”, June 2002. http://www.gr.nl/pdf.php?ID=429; US NIH “Stem
Cells: A primer” September 2002 http://www.nih.gov./news/stemcell/primer.htm.
Shamblott, M.J. et al. “Human embryonic germ cell derivates express a broad range of developmentally
distinct markers and proliferate extensively in vitro”, Proc Natl Acad Sci USA, 2001, 98: 113-8.
Jiang, Y. et al., “Pluripotency of mesenchymal stem cells derived from adult marrow”, Nature, 2002 ,
418 : 41-49.
Steindler, D.A. and Pincus D.W., “Stem cells and neuropoiesis in the adult brain”, Lancet, 2002,
359(9311):1047-1054.
17
18
19
18
also been reported that stem cells can be obtained following autopsy, from post
mortem brain tissue for example.
–
Foetal organs or tissues: Foetal tissue or organs obtained after pregnancy termination
can be used to derive stem cells, e.g. neural stem cells which can be isolated from
foetal neural tissue and multiplied in culture.
–
Umbilical cord blood: Haematopoïetic stem cells can be retrieved from the umbilical
cord blood at birth. Stem cells, which could give rise to other tissues, may also be
present in cord blood.
1.2.
Plasticity of human somatic stem cells
Figure 2
PLASTICITY OF STEM CELLS
Stem cell
Dedifferentiation?
Transdifferentiation?
Precursor Cell
Differentiation
Differentiated Cell
Adapted after
D. Steindler,
The University of Florida
e.g. Blood
Or Brain Cells
It has recently been reported that for example:
–
Brain stem cells may differentiate into blood cells20
–
Bone marrow stem cells in vitro may differentiate into neurons, skeletal and cardiac
muscle cells and liver cells etc.21
This later process might be explained by the persistence of very rare pluripotent stem cells
through life, which under normal conditions are “dormant”. However, other hypotheses are
envisaged. The potential of a stem cell may not be defined once and forever but may depend
on the cellular environment. For example a somatic stem cell might be able to make more
than one tissue by one of the following ways:
20
21
Bjornson, C et al., “Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells”,
in vivo. Science, 1999, 283, 354-357.
Jiang Y, et al., “Pluripotency of mesenchymal stem cells derived from adult marrow”, Nature, 2002,
418:41-49; Orlic, D et al., “Bone marrow cell regenerate infarcted myocardium”, Nature, 2001, 410,
701-705; Petersen, B.E. et al., “Bone marrow as a potential source of hepatic oval cells. Science, 1999,
284, 1168-1170.
19
In a changed environment, the original stem cell might dedifferentiate and then be
reprogrammed to generate the alternative cell types
or
The original cell might change directly into another cell type without going through a
dedifferentiated intermediate stage, a process sometimes called “transdifferentiation”.
This is little short of a revolutionary concept in developmental cell biology where it has
generally been considered that in mammalian cells, contrary to plants and lower microorganisms, the process of differentiation was irreversible.
Some scientists question the plasticity of stem cells22. Current research is aimed at
determining the mechanisms that underlie somatic stem cell plasticity. If such mechanisms
can be identified and controlled, existing stem cells from healthy tissue might be induced to
repopulate and repair a diseased tissue23.
1.3.
Potential application of human stem cell research
Transplantation of haematopoïetic stem cells (from bone marrow, peripheral blood or
umbilical cord blood of healthy donor) has been used for more than a decade to treat e.g.
haematological malignancies such as leukemia or congenital immunodeficiencies. Autologous
transplantation (transplantation of stem cells from the patient’s own bone marrow or
peripheral blood) was introduced to rescue the bone marrow of patients who had received
high dose of chemotherapy. It is now increasingly being used as primary treatment for other
types of cancer such as breast cancer and neuroblastoma. Autologous transplantation is also
used experimentally to treat difficult auto-immune conditions and as a vehicle for gene
therapy. Today, over 350 centres in Europe are performing more than 18 000 bone marrow
transplants a year 24.
Human stem cell research is expected to be of interest for several areas of science and
medicine 25:
For the development of novel stem cell based therapies.
–
Novel stem cell based therapies (often called regenerative medicine or cell based
therapies) are also being investigated to develop new methods to repair or replace
tissues or cells damaged by injuries or diseases and to treat serious chronic diseases,
such as diabetes, Parkinson’s, chronic heart failure or stroke and spinal cord injuries.
(See chapter 1.4 for further details)
–
For the generation of normal human cell lines to be used in drug development at
the preclinical stage and in toxicology Stem cells are a source for the generation of
normal human cell types that can be genetically or pharmacologically manipulated
22
Wagers A.J. et al., “Little evidence for developmental plasticity of adult haematopoïetic stem cells”,
Science, 2002, 297, 2256 2259; De Witt and Knight, “Biologists question adult stem cell versality”,
Nature, 2002, 416, 354.
US NIH, “Stem Cells: A primer”, September 2002 http://www.nih.gov./news/stemcell/primer.htm
A. L Lennard and G H Jackson. “Science, medicine and the future: Stem cell transplantation”, BMJ,
2000, 321:433-437.
US NIH, “Stem Cells: A primer”, September 2002 http://www.nih.gov./news/stemcell/primer.htm
Annex E - Opinion n° 15 of the European Group on Ethics http://europa.eu.int/comm/
european_group_ethics/docs/avis15_EN.pdf
23
24
25
20
and used for drug discovery. They give scientists the ability to experimentally study under carefully controlled conditions - the growth and development of many
different human cell types that are important to diseases like cancer, diabetes, stroke,
heart disease etc. These cell lines may provide more clinically relevant biological
systems than animal models for drug testing and are therefore expected to contribute
to the development of safer and more effective drugs for major human diseases. For
example today, there exists no laboratory model for the human heart, and it is
therefore very difficult (impossible) to know exactly what effect medicines have on
the heart before performing human studies. The lack of availability of human cells,
which express normal function, has so far been the main limiting factor for reducing
animal testing in pharmaco-toxicology. It is possible that this application will turn
out to be the major medical impact of human ES cell research at least in a short-term
perspective. At present insufficient methods exist in some areas of in vitro toxicology
predicting target organ toxicity. In other areas such as embryo-toxicity inter-species
variation presents major obstacles and humanised systems may enhance the hazard
identification of chemicals.
–
Use of stem cells in gene therapy: Stem cells could be used as vehicles i.e. bearers of
genetic information for the therapeutic delivery of genes. A problem for research on
gene therapy has been to find safe delivery systems and stem cells may provide a
solution here. At present, experiments are being done with gene therapy to treat
diseases of the blood system. Their aim is to introduce new healthy genes in the
blood-forming stem cells, which can then develop into all types of blood cells and,
moreover, are able to renew themselves and thereby provide a permanent cure.
–
For understanding of human development. Studies of human embryonic and foetal
stem cells may yield a deeper understanding of evolutionary biology and the process
leading from embryo to human being. Human ES cells should offer insights into
developmental events that cannot be studied directly in the intact human embryo but
that have important consequences in clinical areas, including birth defects, infertility,
and pregnancy loss. Particularly in the early post implantation period, knowledge of
normal human development is largely restricted to the description of a limited
number of sectioned embryos and to analogies drawn from the experimental
embryology of other species. Although the mouse is the main stay of experimental
mammalian embryology, early structures including the placenta, extra-embryonic
membranes, and the egg cylinder all differ substantially from the corresponding
structure of the human embryo.
–
For understanding of the basic mechanisms of cell differentiation and
proliferation. A primary goal of this work is to identify how undifferentiated stem
cells become differentiated into particular types of cells. Scientists know that turning
genes on and off are central to this process and molecules such as growth factors and
nutrients, that function during embryonic development, also play a role. This
knowledge can be used to grow stem cells from various sources in the laboratory and
direct their differentiation into specialized cell types. Some of the most serious
medical conditions, such as cancer, are due to abnormal cell division and
differentiation. A better understanding of the genetic and molecular controls of these
processes may yield information about how such diseases arise and suggest new
strategies for therapies.
21
1.4.
Novel stem cell based therapies
Three therapeutic concepts are currently being envisaged 26:
–
Transplantation of differentiated cells derived from stem cells: Stem cells may be
grown and directed to differentiate into specific cell types in the laboratory and then
be transplanted e.g. insulin producing cells to treat diabetes, skeletal muscle cells for
muscle diseases, dopamine producing neurons for Parkinson’s disease etc. The
source for the specific differentiated cell types could be embryonic or somatic stem
cells including the patient’s own stem cells.
–
Direct administration of stem cells: In some cases it may be possible and/or necessary
to administer stem cells directly to the patient in such a way that they would colonise
the correct site of the body and continuously differentiate into the desired cell type
(e.g. systemic “Homing”).
Figure 3
Three potential therapeutic approaches for stem cell
based therapy for brain disorders
Intra-brain injections of stem
cell derived differentiated
neural cells
Stimulation of the patient’s
own stem cells by factors
such as “Neuropoietins”
Direct administration of
stem cells i.e. systemic
“Homing”
Adapted after D. Peace
and D. Steindler
–
1.5.
Stimulation of endogenous stem cells: The possibility that self-repair could be
induced or augmented by stimulating an individual’s own population of stem cells
for example by administrating growth factors is also being explored.
Scientific and technical obstacles to overcome before realising the potential
clinical uses of novel human stem cell based therapy
The novel stem cell based therapies as described in chapter 1.4. are still at a an early stage of
development. In particular regarding the transplantation of differentiated cells derived from
stem cells several scientific and technical hurdles need to be resolved before clinical
application of these therapies, including 27:
26
27
“La recherche sur les cellules souches embryonnaires”, Commission national d’éthique suisse pour la
médicine humaine, Prise de position n° 3/2002; Steindler, D.A. and Pincus D.W., “Stem cells and
neuropoiesis in the adult brain”, Lancet, 2002, 359(9311):1047-1054.
US NIH, “Stem Cells: A primer”, September 2002 http://www.nih.gov./news/stemcell/primer.htm;
House of Lords Select Committee – Report on Stem cell research, February 2002
22
–
Differentiation, dedifferentiation and transdifferentiation: There is still a strong
need to gain a better understanding of the underlying mechanisms regulating stem
cell growth, migration, fate and differentiation in order to ensure controlled and
stable differentiation. If somatic stem cells are dedifferentiated to enhance their
normal potential, scientists must be able to control this process.
–
Inappropriate tissue development: One possible risk of clinical use of stem cell
transplantation is that the cells will not simply grow into replacement or supportive
tissue, but inappropriate differentiated tissue will develop.
–
Tumorigenicity: The risk of tumour development does present an important risk, in
particular if human ES cells are transplanted directly to the patient, as human ES
cells do form teratoma.
–
Isolation and purification: The isolation of many adult stem cells is still difficult.
Purification methods need to be developed in order to avoid the transplant of
inappropriate cells.
–
Immune rejection: The human body possesses an immune system, which recognises
cells that are not its own and rejects them for example following transplantation of
organs, tissues or cells derived from other individuals (heterologous transplantation).
Immune rejection is one of the major causes of transplant failure, and is one of the
problems which will need to be overcome for stem cell-based therapy to be effective
except in the case where the patient’s own stem cells can be used. Different
approaches are currently being envisaged to overcome immune rejection e.g.
immuno-suppressive drugs, generation of immunotolerance, use of “matching tissues
or by somatic cell nuclear transfer (i.e. therapeutic cloning) as described in annex B.
–
Function and viability: The stem cells or their derivatives must function
appropriately for the duration of the recipient’s life and survive in the recipient after
transplantation. Methods to improve and properly assess the viability and functioning
of the differentiated cells need to be worked out.
–
Culture conditions: Good manufacturing practice (GMP) needs to be defined
including the establishment of germ-free culture conditions for the derivation and
differentiation of specialised cell types.
1.6.
Examples of novel stem cell based therapies, which are currently subject to
extensive research.
Neurological diseases and disorders (see also figure 3)
Parkinson’s disease (PD) is caused by a progressive degeneration and loss of dopamine (DA)producing neurons, which leads to rigidity, hypokinesia (abnormally decreased mobility) and
tremor.
Scientists are developing a number of strategies for producing dopamine neurons from human
stem cells in the laboratory for transplantation into humans with Parkinson’s disease including
http://www.parliament.the-stationery-office.co.uk/pa/ld200102/ldselect/ldstem/83/8301.htm ;
The
Health Council of the Netherlands’ report on “Stem cells for tissue repair. Research on therapy using
somatic and embryonic stem cells”, June 2002. http://www.gr.nl/pdf.php?ID=429.
23
the use of neural dopamine producing cells derived from aborted foetuses. Clinical trials in
patients with Parkinson’s disease have been performed on around 200 patients over the last 10
years especially in Sweden and in USA. They have shown that the transplantation of neural
cells derived from the human foetus can have a therapeutic effect, with an important reduction
of the symptoms of the disease in the treated patients28. However, the availability of neural
foetal tissue is very limited. Efforts are now being made to expand fetal neural stem cells and
control their differentiation into dopaminergic neurons.
In a recent study, scientists directed mouse embryonic stem cells to differentiate into
dopaminergic neurons by treatment with growth factors and by introducing the gene Nurr1.
When transplanted into the brains of a rat model of Parkinson’s disease these stem cellderived dopaminergic neurons re-innervated the brains of the rat, released dopamine and
improved motor function.29
The possibility to stimulate the patient’s own stem cells in the brain is also being explored.
Self-repair could be induced or augmented with neuro-poïetins - small selective growth
factors that trigger repair processes by an individual’s own indigenous population of stem
cells 30.
Heart failure
When heart muscle cells (cardiomyocytes) are destroyed, e.g. after a heart attack, functional
contracting heart muscle is replaced with non-functional scar tissue. It is hoped that healthy
heart muscle cells generated in culture in the laboratory and then transplanted into patients
could be used to treat patients with e.g. chronic heart disease.
Recent research in mice indicates that mouse cardiomyocytes derived from mouse embryonic
stem cells, transplanted into a damaged heart, can generate new heart muscle cells and
successfully repopulate the heart tissue. These results suggest that cardiomyocytes derived
from human embryonic stem cells derived could be developed for cell transplantation therapy
in humans suffering from heart failure31.
It has also been reported from animal studies that bone marrow stem cells 32 have the potential
to be used to repair the infarcted heart. The transplantation of autologous bone marrow cells
(transplantation of the patient’s own stem cells) into the infected heart has been reported in
two small non randomized human studies 33.
28
29
30
31
32
33
Bjorklund, A. and Lindvall O., “Cell replacement therapies for central nervous system disorders”,
Nature Neuroscience, 2000, 3, 537-544.
Björklund, L. M. et al. “Embryonic stem cells develop into functional dopaminergic neurons after
transplantation in a Parkinson rat model”, Proc. Natl. Acad. Sci. USA , 2002, 99:2344-2349; Kim J-H.
et al., “Dopamine neurons derived from embryonic stem cells function in an animal model of
Parkinson’s disease”, Nature, 2002, 418: 50-56.
Steindler, D.A. and Pincus D.W., “Stem cells and neuropoiesis in the adult brain”, Lancet, 2002,
359(9311):1047-1054.
Kehat et al., “Human embryonic stem cells can differentiate into myocytes with structural and
functional properties”, J Clin Invest, 2001, 103:407-14.
Orlic, D. et al. “Bone marrow cells regenerate infarcted myocardium”, Nature, 2001, 410, 701-705.
Orlic, D. et al. “Mobilized bone marrow cells repair the infacted heart, improving function and
survival”, Proc Natl Acad Sci USA 2001, 98: 10344-9.
Assmus, B. et al. “Transplantation of progenitor cells and regeneration enhancement in acute
myocardial infarction (TOPCARE-AMI)”, Circulation, 2002, 106: R53-R61; Strauer, B.E. et al.
24
Diabetes
In people who suffer from type I diabetes, the cells of the pancreas that normally produce
insulin are destroyed by the patient’s own immune system. Although diabetics can be treated
with daily injections of insulin, these injections enable only intermittent glucose control. As a
result, patients with diabetes suffer chronic degeneration of many organs, including the eye,
kidney, nerves and blood vessels. In some cases, patients with diabetes have been treated with
islet beta cell transplantation. However, poor availability of suitable sources for islet beta cell
transplantation from post mortem donors makes this approach difficult as a treatment for the
growing numbers of individuals suffering from diabetes.
Ways to overcome this problem include deriving islet cells from other sources such as:
–
Human adult pancreatic duct cells that have been grown successfully in vitro and
induced to differentiate, but the ability of these cells to restore blood glucose in vivo
is still unproven. This promising line of research is being pursued by several
laboratories.
–
Fetal pancreatic stem cells and ß cell precursor. The identification of endocrine
precursor cells in the developing pancreas and the regulation of their differentiation
by a specific cellular pathway raises the possibility to grow and differentiate
endocrine precursor cells in vitro taken from aborted foetus or by using adult
pancreatic duct cells34.
–
Embryonic stem cells. Research in mice has demonstrated that mouse embryonic stem
cells can differentiate into insulin- producing cells and other pancreatic endocrine
hormones. The cells self-assemble to form three-dimensional clusters similar in
topology to normal pancreatic islets. Transplantation of these cells was found to
improve the conditions of experimental animals with diabetes35. New studies indicate
that it is possible to direct the differentiation of human embryonic stem cells in cell
culture to form insulin-producing cells.
34
35
“Repair of infarcted myocardium by autologous intracoronary mononuclear bone narrow cell
transplantation in humans”, Circulation, 2002, 106: 1913-1918.
Serup P. et al. “Islet and stem cell transplantation for treating diabetes”, BMJ, 2001, 322:29-32.
Lumelsky, N. et al. “Differentiation of embryonic stem cells to insulin - secreting structures similar to
pancreas islets”, Science, 2001, 292: 1389-94.
25
Chapter 2: Human embryonic stem cell research
2.
CHAPTER 2: HUMAN EMBRYONIC STEM CELL RESEARCH
The first embryonic stem cells were isolated from mice in 1981 and a great deal of research
has been undertaken on mouse embryonic stem cells. A new era of stem cell biology began in
1998, when the derivation of embryonic stem cells from human blastocysts was first
demonstrated36. Since then, several research teams have been working on the characterisation
of these cells and on improving the methods for culturing them.
2.1.
Origin and characteristics of human embryonic stem cells
Human embryonic stem cells can be derived from preimplantation embryo at the blastocyst
stage. At this stage, which is reached after about 5 days’ embryonic development, the embryo
appears as a hollow ball of 50-100 cells, called the blastocyst. The blastocyst includes three
structures: the outer cell layer, which will develop into the placenta; the blastocoel, which is
the fluid filled cavity inside the blastocyst; and the inner cell mass, from which the human ES
cells can be isolated.
The characteristics of human embryonic stem cells include:
- Potential to differentiate into the various cell types in the body (more than 200 types are
known) even after prolonged culture. The human ES cells are referred to as pluripotent.
- Capacity to proliferate in their undifferentiated stage.
2.2.
Possible sources for human embryonic stem cells
Human embryonic stem cells can be isolated from preimplantation embryos (blastocysts)
created by different in vitro techniques37 (i.e. embryos created outside the human body; these
embryos cannot develop beyond the blastocyst stage without implantation into the uterus):
1. Supernumerary embryos:
One possible source would be to use supernumerary embryos. These are embryos, which have
been created by means of in vitro fertilisation (IVF) for the purpose of assisted reproduction
but subsequently not used. In by far the majority of cases, assisted reproduction is used in
connection with fertility problems, where supernumerary embryos may be created in order to
increase the success of infertility treatment. In the countries where pre-implantation diagnosis
is allowed, IVF is also used in connection with this practice and human ES cells can also be
derived from embryos, which are discarded following pre-implantation diagnosis. These
supernumerary embryos may be donated for research by the couples concerned with their
fully informed consent.
36
37
Thomson, J.A. et al. “Embryonic stem cell lines derived from human blastocysts”, Science, 1998, 282,
1145-1147.
Thomson, J.A. et al. “Embryonic stem cell lines derived from human blastocysts”, Science, 1998, 282,
1145-1147. Annex E - Opinions n°15 and 16 of the European Group on Ethics
http://europa.eu.int/comm/european_group_ethics/docs/avis15_en.pdf
http://europa.eu.int/comm/european_group_ethics/docs/avis16_en.pdf
26
2. Embryos created by IVF for research purposes and/or for the purpose of stem cell
procurement 38:
Embryos created for the purpose of research may be produced with donated gametes, i. e. they
are created by in vitro fertilisation of a human egg by human sperm.
3. Embryos created by somatic cell nuclear transfer for research purposes and/or for the
purpose of stem cell procurement 39:
Embryos may be produced by somatic cell nuclear transfer i.e. they are created by introducing
the nucleus of an adult somatic cell (e.g. a cell from the patient) into an enucleated human
oocyte and then activating the egg’s further development without fertilisation (often referred
to as therapeutic cloning). When the blastocyst stage is reached pluripotent stem cells can be
isolated and cultured. These later stem cells have the advantage of being immunologically
compatible with the patient. Laboratories currently attempt to replace the nuclei of human ES
cell in culture by somatic nuclei from patients’ cells in order to overcome the problem of
immune rejection.
4. Other possibilities:
It is also possible to obtain human ES cells by parthenogenesis (by stimulation in vitro of an
egg cell to initiate the duplication of the egg’s genetic information and then the division of the
cell). Finally, it is speculated that ES cells may possibly be obtained by injecting stem cell or
egg cytoplasm into differentiated cells transforming these cells into pluripotent stem cells
(ovoplasmic transfer).
It is possible that new ways of deriving human ES cells could be developed in the future.
2.3.
Growing human embryonic stem cells in the laboratory40
In order to derived embryonic stem cells, the outer membrane of the blastocyst is punctured,
whereupon the inner cell mass with its stem cells is collected and transferred into a laboratory
culture dish that contains a nutrient broth known as culture medium. The blastocyst is thereby
destroyed and cannot develop further, but the isolated human ES cells can be cultivated in
vitro and give rise to stem cell line. The stem cell lines can be cryopreserved and stored in a
cell bank. To be successful, the cultivation requires, in addition to nutrient solution, so-called
“feeder” cells or support cells. Until recently fibroblasts from mice have been used for this
purpose, however scientists are now able to propagate human ES cell lines using human
feeder layer or even culturing human ES cells without feeder layer. This eliminates the risk
that viruses or infectious agents in the mouse cells might be transmitted to the human cells.
If the stem cells are of good quality and if they show no sign of ageing, the same stem-cell
line can yield unlimited amounts of stem cells. Besides their broad potential for
38
39
40
In accordance with the Council decision of 30 September adopting the specific programmes
implementing FP 6 the creation of embryos for research purposes and for stem cell procurement,
including by means of somatic cell nuclear transfer (i.e. therapeutic cloning) are excluded from funding
under the 6th Framework Programme. OJ L 294 of 29.10.2002, p. 8.
In accordance with the Council decision of 30 September adopting the specific programmes
implementing FP 6 the creation of embryos for research purposes and for stem cell procurement,
including by means of somatic cell nuclear transfer (i.e. therapeutic cloning) are excluded from funding
under the 6th Framework Programme. OJ L294 of 29.10.2002, p. 8.
US NIH, “Stem cells: a primer”, September 2002. http://www.nih.gov./news/stemcell/primer.htm
Swedish National Council on Medical Ethics: statement of opinion on embryonic stem cell research,
17.01.2002, http://www.smer.gov.se.
27
differentiation, embryonic stem cell lines have proved better able to survive in the laboratory
than other types of stem cells. At the various points during the process of generating
embryonic stem cell lines, scientists test the cells to see whether they exhibit the fundamental
properties that make them, embryonic stem cells. As yet, there exists no standard battery of
tests that measure the cells’ fundamental properties but several kinds of tests including tests
based on the presence of specific surface and gene markers for undifferentiated cells.
One can distinguish:
–
Human ES cells freshly derived from an embryo which have not yet been subjected
to any modification and which have yet to be established as stem cell lines.
–
Unmodified (undifferentiated) human ES cell lines, which refer to cultured lines of
cells, which have been propagated for an extended period originally from freshly
human ES cells and which have not been modified in any other way.
–
Modified (differentiated) human ES derivates which refer to cultured lines of cells,
derived from human ES cells or human ES cell lines, which have been modified
either by genetic manipulation, or by treatment (e.g. growth factors) that causes the
cells to differentiate in a particular way e.g. to differentiate into neural or muscle
precursor cells (cells which are not fully differentiated, otherwise they will not
multiply).
2.4.
The current advantages and limitations of human embryonic stem cells and
human somatic stem cells
In light of current knowledge, human embryonic and somatic stem cells each have advantages
and limitations regarding potential use for basic research and stem cell based therapy.
2.4.1.
Human embryonic stem cells
Advantages:
–
human ES cells have the potential to generate the various cell types in the body (they
are pluripotent).
–
human ES cells are at present the only pluripotent stem cell that can be readily isolated
and grown in culture in sufficient numbers to be useful.
Limitations:
–
The most significant potential scientific limitation on the therapeutic use of human ES
cells is the problem of immune rejection. Because human ES cells will not normally
have been derived from the patient to be treated, they run the risk of rejection by the
patient’s immune system. Annex B provides an overview of the possibilities to
overcome immune rejection currently under investigation e.g. immuno-suppresive
drugs, generation of immuno-tolerance, use of “matching tissues” or by somatic cell
nuclear transfer (i.e. therapeutic cloning).
–
It has been argued that, because human ES cells have the potential to differentiate into
all cell types, it might be difficult to ensure that, when used therapeutically, they do
not differentiate into inappropriate cell types or generate tumors. It is clearly
essential to guard against these risks in particular of tumorgenesis.
28
–
2.4.2.
Current methods for growing human ES cell lines in culture are adequate for research
purposes, but the co-culture of human ES cells with animal materials necessary for
growth and differentiation would preclude their use in therapy. Scientists are now
working on generating stem cell lines, which are grown on human feeder layer or
without feeder layer and in completely defined culture media.
Human somatic stem cells
Advantages:
–
The potential of somatic stem cells for therapeutic application is illustrated by the use
of haematopoïetic stem cells to treat leukemias and other blood disorders38.
–
Recent studies suggesting that various somatic stem cells have much greater potential
for differentiation than previously suspected have opened up the possibility that other
routes to somatic stem cell therapy might be available.
–
The patient’s own stem cells could be expanded in culture and then reintroduced into
the patient which would mean that the cells would not be rejected by the immune
system. This represents a significant advantage, as immune rejection is a difficult
problem.
–
In the future it might be possible to stimulate proliferation and fate control of the
patient’s own indigenous somatic stem cell population in-situ by systemicallyintroduced “poïetins”.
Limitations:
–
The isolation, growth and differentiation of adult stem cells have to date proved
difficult. Stem cells generally represent a small proportion of cells in adult tissues. It
should be recognised that although haematopoïetic stem cells represent a small
proportion of cells in the peripheral blood (i.e. haematopoïetic stem cells, 1 out of
100,000 white blood cells), they are now the preferred source of autologous stem
cells for transplantation in adults41.
–
Where a person suffers from a genetic disorder or some types of cancers, somatic stem
cells isolated from that individual will retain the damaging genetic alterations
underlying the disease and so be of little therapeutic value e.g. in the case of
diabetes. However, they could be corrected by gene therapy.
–
It is not yet known whether somatic stem cells give rise to cells of different tissue
types by transdifferentiation, or by dedifferentiation to a less differentiated stem cell,
which then differentiates into the new cell types. The control and safety of
dedifferentiation is a major challenge and one about which little is yet known.
–
Adult stem cells may contain more DNA abnormalities caused by sunlight, toxins and
errors in making more DNA copies during the course of a lifetime.
41
Lennard, A. L. and Jackson G. H., “Science, medicine and the future: Stem cell transplantation”, BMJ,
2000, 321:433-437.
29
It is a matter of debate within the scientific community whether human embryonic stem cells
have a greater potential that human somatic stem cells (isolated from foetal or adult tissue).
The recent reports regarding the plasticity of human somatic stem cells as described earlier in
chapter 1.2, have led to the question of why embryonic stem cell research is needed if somatic
stem cells are available. These issues have been exhaustively considered in many national
reports from advisory bodies, ethics committees, learned societies etc. and in scientific
publications. The conclusions of these reports published in the recent months have
highlighted that it is too early to know what findings will come from embryonic or somatic
stem cell research and which stem cells will best meet the needs of basic research and clinical
application42.
2.5.
Examining the need for new human embryonic stem cell lines.
The question whether there are already enough embryonic stem cell lines that meet the
criteria, which are considered ethically acceptable by Member States, is important in the
debate. Although human embryonic stem cell lines have been registered, in particular at the
US National Institutes of Health Human embryonic stem cell registry (see 2.6)43 several
arguments have been put forward regarding the needs for derivation of new human embryonic
stem cell lines44:
–
Human embryonic stem cell research is so new that scientists do not yet know if they
have developed the best procedures for isolating or maintaining human ES cells. It is
possible that all the current cell lines are compromised, as happened with the first
mouse ES cell lines.
–
Many of the human embryonic stem cell lines currently available have not been
sufficiently verified to see whether they exhibit the fundamental properties that make
them embryonic stem cells e.g. the six human ES cell lines from the Karolinska
Institute currently at the NIH registry are not available and have not yet been fully
characterized 45 (see annex C for further information).
–
Most currently available human ES cell lines have been cultivated in contact with
mouse cells. The contact with animal cells and serum components involves an
unknown risk of contamination with viruses and other infectious agents. Therefore,
such cell lines or their derivatives can not be used for transplantation to humans.
42
“Stem Cells: scientific progress and future research directions”, National Institutes of Health (NIH),
Bethesda, USA, June 2001 http://www.nih.gov/news/stemcell/scireport.htm; Swiss National Advisory
Commission on Biomedical Ethics: opinion on human embryonic stem cell research, June 2002; The
Health Council of the Netherlands’ report on “Stem cells for tissue repair. Research on therapy using
somatic and embryonic stem cells”, June 2002. http://www.gr.nl/pdf.php?ID=429; House of Lords
Select Committee UK “Report on Stem cell research”, February 2002; http://www.parliament.thestationery-office.co.uk/pa/ld200102/ldselect/ldstem/83/8301.htm ; Swedish National Council of
Medical Ethics: Statement of opinion on embryonic stem cell research, 17.01.2002.
http://escr.nih.gov/eligibilitycriteria.html. The US National Institute of Health (NIH) has identified 78
human embryonic stem cell lines that meet the US eligibility criteria. The availability and the stage of
development and characterisation of these human ES cell lines are unclear and the NIH has now
indicated 9 human ES cell lines which are available for distribution to different laboratories. (James
Battery, Head of NIH panel managing stem cell research). Science 2003 (299) 1509. The Wisconsin
Alumni Research Foundation, which owns five stem cell lines, claims that it has enough to supply all
scientists in the world.
e.g. The Health Council of the Netherlands’ report on “Stem cells for tissue repair. Research on therapy
using somatic and embryonic stem cells”, June 2002. http://www.gr.nl/pdf.php?ID=429.
Communication from Carlstedt-Duke, Dean of Research, Karolinska Institute, Sweden.
43
44
45
30
–
Currently available human ES cell lines represent only limited amount of genetic
variation. It is important to notice that cell lines with a different genetic basis can
have different characteristics.
–
Many of the existing embryonic stem cell lines have been patented in the US. It is
important not to be in a dependent position with respect to private industry.
Annex C provides examples of the currently available human ES cell lines.
2.6.
Developments regarding establishment of human stem cell banks and registries.
Human stem cell banks
The need for public stem cell banks including human embryonic stem cell has been
recognised at national level both in Sweden and UK.
The British Medical Research Council (MRC) in autumn 2002, in collaboration with the
Biotechnology and Biological Science Research Council (BBSRC) and with the full backing
of the UK Government, took the initiative to establish the first large-scale publicly funded
Stem Cell Bank worldwide. The National Institute for Biological Standards and Control
(NIBSC) is hosting the UK Stem Cell Bank 46, which officially started 1 January 2003.
The general aim of the UK Stem Cell Bank will be to create an independent and competent
facility to store, test and release seed stocks of existing and new stem cell lines derived from
adult, foetal and embryonic human tissues. There will be two primary components in this
work:
1)
To provide stocks of well-characterised stem cell lines for use in research in the UK
and abroad. These will be established under well regulated, but non-GMP, conditions
and made available in order to promote fundamental research.
2)
To provide stocks of stem cell lines prepared under GMP conditions, that could be
used directly for production of human therapeutic materials.
In February 2002, the Human Fertilisation and Embryology Authority (HFEA) in the UK
granted the first two licences for embryo research under the 2001 Regulation to Imperial
College in London and the University of Edinburgh. The protocols approved will create
human embryonic stem cell lines from embryos originally created for IVF treatment but
subsequently donated for research. At the time of writing this report no human ES cell lines
had as yett been derived. When generated the cell lines will be placed in the UK stem cell
bank. This is a requirement of HFEA research licence.
The Karolinska Institute in Stockholm is also planning to establish a Stem Cell Bank, based
on the various stem cell lines established at the Institute (about 9 human ES cell lines are
expected to be available within the next 12 months). These lines will be available for other
scientists worldwide 47.
Human ES cell research is also ongoing at the Sahlgrenska Academy, Gothenburg University,
Sweden in collaboration with Cell Therapeutics Scandinavia, AB. The two centres are active
46
47
http://www.nibsc.ac.uk/divisions/cbi/stemcell.html
Communication from Professor Carlstedt-Duke, Dean of Research, Karolinska Institute, Sweden
31
in generating human ES cell lines as well as in developing differentiated normal human cells.
21 human ES cell lines have so far been established. Four of these have been fully
characterized and two of these four fulfil all the criteria for self-renewal and pluripotency of
human ES cells. The remaining 17 cell lines have been partially characterized48.
Extensive human ES cell research is taking place outside the EU in particular, in the USA,
Australia, Israel, Singapore, Korea and China. As far as the Commission is informed it is for
the moment only the UK and Sweden that are planing to establish public stem cell banks.
The stem cell bank intends not only to provide high quality starting materials to facilitate the
development of stem cell therapy, but, in providing a centralised resource for researchers, it
will optimise the use of existing human embryonic stem cell lines and may reduce the use of
human embryos for the development of new stem cell lines by individual teams. It will also
offer the opportunity to collect stem cell lines with different immuno- phenotypes. Cell lines
with the best matching phenotypes can later be selected for cell or tissue transplantation.
Human embryonic stem cell registry
The US National Institutes of Health (NIH) established in autumn 2001 an Human Embryonic
Stem Cell Registry which at present lists 78 human ES cell lines that meet the eligibility
criteria for Federally funded research49. The registry indicates 14 laboratories or companies
across the world, which have developed human embryonic stem cell lines. The availability of
these cell lines and their level of characterisation are unclear and the NIH Human Embryonic
Cell Registry has recently been updated to reflect the human ES cell lines that meet the
eligibility criteria for Federally funded research and which are currently available for shipping
to other laboratories50. This list includes 9 human ES cell lines:
2 human ES cell lines from BresaGen, Inc. (a US based company)
5 human ES cell lines from ES Cell International (a company based in Singapore and
Australia)
1 human ES cell line from University of California at San Francisco
1 human ES cell line from Wisconsin Alumni Research Foundation
Both the European Group on Ethics in Science and New Technologies51 and the European
Group on Life Sciences52 have highlighted the need for a European registry of stem cell lines.
In particular, the EGE called in their opinion n°16 on “Ethical aspects of patenting inventions
involving human stem cells” for the creation of an EU registry of unmodified human stem cell
lines.
48
49
50
51
52
Communication from Professor Hamberger, Goteborg University, Sweden.
http://escr.nih.gov/eligibilitycriteria.html. The following eligibility criteria must be met: (i) the
derivation process has been initiated before 9 August 2001; (ii) the stem cells must have been derived
from an embryo that was created for reproductive purposes but the embryo was not longer needed for
those purposes; (iii) informed consent must have been obtained for the donation of the embryo; (iv) no
financial inducements were provided for donation of the embryo.
http://escr.nih/
http://europa.eu.int/comm/european_group_ethics/docs/avis16_en.pdf
http://europa.eu.int/comm/research/life-sciences/egls/index_en.html
32
“Such registry, which should include information on both embryonic stem cells and
embryonic germ cell lines should be publicly accessible. Its aim would be to ensure
transparency and thus facilitate access by the research community to the needed biological
material for further research”51
33
Chapter 3: Governance of human embryonic stem cell research
3.
CHAPTER 3: GOVERNANCE OF HUMAN EMBRYONIC STEM CELL RESEARCH
Human embryonic stem cell research raises complex ethical questions. It confronts scientific
progress with ethical concerns and it has triggered an intense public debate on its guiding
ethical principles and limitations. The question whether it is ethically defensible to do
research on embryonic stem cells can be described as a conflict between different values,
between different actors’ rights and obligations, or between the short- and long-term interests
of different groups. On the one hand, there is interest in new knowledge that can lead to
treatment of hitherto incurable diseases. On the other hand, when this research involves the
use of human embryos, it raises the question of ethical values at stake and of the limits and
conditions for such research53. Opinions on the legitimacy of experiments using human
embryos are divided according to the different ethical, philosophical, and religious traditions
in which they are rooted. EU Member States have taken very different positions regarding the
regulation of human embryonic stem cell research. This confirms that different views exist
throughout the European Union concerning what is and what is not ethically defensible.
3.1.
The ethical issues at stake
The European Group on Ethics highlighted in its Opinion No.15 regarding “Ethical aspects of
human stem cell research and use”, issued 14 November 200054, that “the fundamental ethical
principles applicable to stem cell research are:
–
The principle of respect for human dignity
–
The principle of individual autonomy (entailing the giving of informed consent, and
respect for privacy and confidentiality of personal data)
–
The principle of justice and of beneficence (namely with regard to the improvement
and protection of health)
–
The principle of freedom of research (which is to be balanced against other
fundamental principles)
–
The principle of proportionality (including that research methods are necessary to the
aims pursued and that no alternative more acceptable methods are available).
In addition, the Group considers it important to take into account, based on a precautionary
approach, the potential long-term consequences of stem cell research and use for individuals
and the society.”
Concerning the creation of embryos for research purpose the EGE considered that “the
creation of embryos for the sole purpose of research raises serious concerns since it
represents a further step in the instrumentalisation of human life” and deemed “ the creation
53
54
Annex E - Opinion No. 15 of the European Group on Ethics regarding “Ethical aspects of human stem
cell research and use”; http://europa.eu.int/comm/european_group_ethics/docs/avis15_en.pdf
Annex E: Opinion No. 15 of the European Group on Ethics regarding “Ethical aspects of human stem
cell research and use”; http://europa.eu.int/comm/european_group_ethics/docs/avis15_en.pdf
34
of embryos with gametes donated for the purpose of stem cell procurement ethically
unacceptable, when spare embryos55 represent a ready alternative source”.
Furthermore the EGE considered “ that, at present, the creation of embryos by somatic cell
nuclear transfer for research on stem cell therapy would be premature, since there is a wide
field of research to be carried out with alternative sources of human stem cells (from spare
embryos, foetal tissues and adult stem cells”.
The ethical acceptability of human embryonic stem cell research in the context of
Community Framework Programme for Research
The EGE noted in the same opinion that “in some countries embryo research is forbidden. But
when this research is allowed, with the purpose of improving treatment for infertility, it is
hard to see any specific argument, which would prohibit extending the scope of such research
in order to develop new treatments to cure severe diseases or injuries. As in the case of
research on infertility, stem cell research aims to alleviate severe human suffering. In any
case, the embryos that have been used for research are required to be destroyed.
Consequently, there is no argument for excluding funding of this kind of research from the
Framework Programme of research of the European Union if it complies with ethical and
legal requirements as defined in this programme”.
Secondly the EGE stated, that:
“Stem cell research based on alternative sources (spare embryos, foetal tissues and adult
stem cells) requires a specific Community research budget. In particular, EU funding should
be devoted to testing the validity of recent discoveries about the potential of differentiation of
adult stem cells. The EU should insist that the results of such research be widely disseminated
and not hidden for reasons of commercial interest.
At European Union level, within the Framework Programme of research, there is a specific
responsibility to provide funding for stem cell research. This implies the establishment of
appropriate procedures and provision of sufficient means to permit ethical assessment not
only before the launching of a project but also in monitoring its implementation.”
Principal requirements regarding human embryonic stem cell research.
Concerning the use of human supernumerary embryos as a source of stem cells the EGE
stressed in their opinion that “ the derivation of stem cells from embryonic blastocysts raises
the issue of the moral status of the human embryo. In the context of European pluralism, it is
up to each Member State to forbid or authorise embryo research. In the latter case, respect
for human dignity requires regulation of embryo research and the provision of guarantees
against risks of arbitrary experimentation and instrumentalisation of human embryos”.
The EGE also stressed regarding stem cell research and rights of women that “Women who
undergo infertility treatment are subject to high psychological and physical strain. The group
stresses the necessity to ensure that the demand for spare embryos (supernumerary embryos)
and oocyte donation does not increase the burden on women”.
55
Spare embryos: another word for supernumerary embryos.
35
The EGE stressed also the importance of the following requirements regarding human
embryonic stem cell research and the procurement of embryonic stem cells from
supernumerary embryos:
–
Free and informed consent from the donating couple or woman.
The EGE stated: “Free and informed consent is required not only from the donor but also
from the recipient as stated in the Group's opinion on Human Tissue Banking (21/07/1998).
In each case, it is necessary to inform the donor (the woman or the couple) of the possible use
of the embryonal cells for the specific purpose in question before requesting consent.” The
requirements may differ on the type of information that should be provided and on the
definition of which persons should give their consent (the couple or the woman). The Charter
of Fundamental Rights of the European Union recognised in article 3(2) that “In the fields of
medicine and biology the following must be respected in particular – the free and informed
consent of the person concerned, according to the procedures laid down by law…”.
–
Approval of the research by an authority.
The EGE recommended that human ES cell research should be placed, “in the countries
where it is permitted, under strict public control by a centralised authority - following, for
instance, the pattern of the UK licensing body (the Human Fertilisation and Embryology
Authority)” and provided that “ authorisations given to such research are highly selective and
based on a case by case approach, while ensuring maximum transparency. This must apply
whether the research in question is carried out by either the public or the private sector”.
–
No financial gain for donation
The EGE recommended that “The potential for coercive pressure should not be
underestimated when there are financial incentives. Embryos as well as cadaveric foetal
tissue must not be bought or sold, and not even offered for sale. Measures should be taken to
prevent such commercialisation”.
The Charter of Fundamental Rights of the European Union recognised in article 3(2) that “In
the fields of medicine and biology the following must be respected in particular… the
prohibition on making the human body and its parts as such a source of financial gain”.
Article 21 of the Council of Europe Convention on Human Rights and Biomedicine
specifically prohibits financial gain from all or part of the human body.
–
Anonymity of the donors and protection of the confidentiality of personal
information of the donors as it applies for donation of human biological material.
The EGE recommended that “Steps must be taken to protect and preserve the identity of both
the donor and the recipient in stem cell research and use”. As stated in the EGE's Opinion on
Human Tissue Banking (21/07/1998): “in the interests of anonymity, it is prohibited to
disclose information that could identify the donor, and the recipient. In general, the donor
should not know the identity of the recipient, nor should the recipient know the identity of the
donor”. In most cases the donors will not be anonymous in the sense that the embryo could be
traced back to the donor of the egg and sperm. Although the identity of the donor should
normally be protected though coding and other measures to ensure confidentiality, there
would still be safety and quality requirements for clinical research demanding that the link to
the donors not be completely removed. Anonymity will then not be possible.
36
–
Transparency regarding research results.
The EGE recommended in the context of funding stem cell research within the EU
Framework Programmes for Research that “the EU should insist that the results of such
research be widely disseminated and not hidden for reasons of commercial interest”
Concerning clinical research on human stem cells the EGE stressed the importance of the
following requirements:
–
Free and informed consent of the patient and the donor
–
Risk-benefit assessment
“Risk-benefit assessment is crucial in stem cell research, as in any research, but is more
difficult as the uncertainties are considerable given the gaps in our knowledge. Attempts to
minimise the risks and increase the benefits should include optimising the strategies for
safety. It is not enough to test the cultured stem cells or tissues derived from them for
bacteria, viruses or toxicity. Safety and security aspects are of utmost importance in the
transplantation of genetically modified cells and when stem cells are derived from somatic
cells. For example, the risks that transplanted stem cells cause abnormalities or induce
creation of tumours or cancer have to be assessed. It is important that the potential benefits
for the patients should be taken into account but not exaggerated. The grounds of a
precautionary approach need to be taken into account”.
–
Protection of the health of persons involved in clinical trials
“The possibility that irreversible and potentially harmful changes are introduced in clinical
applications of stem cell research should be minimised. Techniques enhancing the
possibilities of reversibility should be used whenever possible. If, for example, genetically
modified cells were encapsulated when they are transplanted in order to stimulate neural cell
growth, it should be possible for the procedure to be reversed if something goes wrong.”
The opinion of the EGE regarding “Ethical aspects of human stem cell research and use”
dates back to 14 November 2000, but it is still considered to be relevant. Human stem cell
research and in particular human embryonic stem cell research are still in an early stage of
development and therefore the fundamental ethical principles at stake and the requirements
for for human embryonic stem cell research are still relevant.
Chapter 3.2 provides further information regarding the requirements applied in EU Member
States allowing for the import and use of human embryonic stem cells and/or the procurement
of human ES cells from supernumerary embryos.
37
3.2.
Regulations in EU Member States regarding human embryonic stem cell
research 56
EU Member States have already taken very different positions regarding the regulation of
human ES cell research and new legislation or regulations are being drafted or debated. Table
1 attempts to provide a comprehensive overview of the situation as of March 2003.
The following distinctions can be made:
1. Allowing for the procurement of human embryonic stem cells from supernumerary
embryos by law
Finland
The medical research Act of 1999 covers the preconditions and use of human embryos up to
14 days of embryonic development. The production of human embryonic stem cells from
supernumerary embryos is allowed. The laboratories that do embryo research need a licence
from the National Authority for Medicolegal Affairs. An ethics committee must approve
research projects. The informed consent of both gamete donors is required.
Greece
The recent law 3089/2002 on medically assisted human reproduction allows for the
procurement of human embryonic stem cells from supernumerary embryos. The Act requires
the informed consent of both gamete donors and no financial inducement.
The Netherlands
The Embryo Act of September 2002 allows the use of supernumerary embryos for research
including isolation of embryonic stem cells from such embryos. This research requires the
favourable opinion of the Central committee for research involving human subjects. The
informed consent of the donor is required. The research must have the aim to lead to new
insights in medical science.
Sweden
The Act of 1991 on “Measures for Purposes of Research and Treatment involving Fertilised
Human Ova” and the Health and Medical Care Act (18-982:763) apply. According to the
Act(1991:115), in vitro embryo research is legally permitted until day 14 after conception,
after which the embryo must be destroyed.. After some discussion there is consensus that this
legislation permits human embryonic stem cell research. A revision of the law is under
discussion (see chapter 3.3)
United Kingdom
The research purposes permitted by the Human Fertilisation and Embryology Act of 1990
were extended by the “Human Fertilisation and Embryology (Research Purposes )
Regulation” of 2001 to permit the use of embryos in research to increase knowledge about
serious diseases and their treatment. The Human Fertilisation and Embryology Authority is
56
European Commission, DG Research, Directorate E: Survey on opinions from National Ethics
Committees or similar bodies, public debate and national legislation in relation to human embryonic
stem cell research and use (last update March 2003); “Survey on the National Regulations in the
European Union regarding Research on Human Embryos” - B. Gratton - published by the Secretariat of
the EGE - European Commission - July 2002.
38
responsible for licensing research involving the creation and use of human embryos. The
HFEA requires the informed consent of the donors and free donation. The first two licences
for stem cell research under the 2001 Regulations were issued by HFEA in February 2002.
2.
Prohibition of the procurement of embryonic stem cells from human embryos
but allowing by law the import and use of human embryonic stem cell lines under
certain conditions.
Germany
The Embryo protection Act of 1990 forbids any research which is not for the benefit of the
concerned embryo.
A new Act ensuring protection of embryos in connection with the importation and utilisation
of human embryonic stem cells – Stem Cell Act – (Stammzellgesetz – StZG) was adopted on
28 June 2002.
Concerning importation and utilisation of embryonic stem cells the act specifies in section 4 , that:
(1) The importation and utilisation of embryonic stem cells shall be prohibited.
(2) Notwithstanding para 1, the importation and utilisation of embryonic stem cells for research purposes shall be
permissible under the conditions stipulated in section 6 if
1. The competent agency has satisfied itself that
a) The embryonic stem cells were derived before 1 January 2002 in the country of origin in accordance with
relevant national legislation there and are kept in culture or are subsequently stored using
cryopreservation methods (embryonic stem cell line)
b) The embryos from which they were derived have been produced by medically-assisted in vitro fertilisation
in order to induce pregnancy and were definitely no longer used for this purpose and that there is no
evidence that this was due to reasons inherent in the embryos themselves.
c) No compensation or other benefit in money’s worth has been granted or promised for the donation of
embryos for the purpose of stem cell derivation and if
2. Other legal provisions, in particular those of the German Embryo Protection Act, do not conflict with the
importation or utilisation of embryonic stem cells.
(3) Approval shall be refused if the embryonic stem cells have obviously been derived in contradiction to major
principles of the German legal system. Approval may not be refused by arguing that the stem cells have been
derived from human embryos.
Concerning using embryonic stem cells section 5 states:
Research involving embryonic stem cells shall not be conducted unless it has been shown by giving scientific
reasons that
1. Such research serves eminent research aims to generate scientific knowledge in basic research or to
increase medical knowledge for the development of diagnostic, preventive or therapeutic methods to be
applied to humans and that,
2. According to the state-of-the-art of science and technology,
a) The questions to be studied in the research project concerned have been clarified as far as possible through
in vitro models using animal cells or through animal experiments and
b) The scientific knowledge to be obtained from the research project concerned cannot be expected to be
gained by using cells other than embryonic stem cells.
Concerning approval section 6 states:
1) Any importation and any utilisation of embryonic stem cells shall be subject to approval by the competent
agency
39
2) Applications for approval must be submitted in writing. In the documents accompanying the application, the
applicant shall provide the following information in particular:
1. Name and official address of the person responsible for the research project concerned,
2. A description of the research project including scientific reasons showing that the research project meets
the requirements set forth in section 5 above,
3. A documentation concerning the embryonic stem cells to be imported or used showing that the
requirements set forth in no. 1 of para 2 of section 4 above have been complied with or equivalent evidence
that
a) The embryonic stem cells to be imported or used are identical with those registered in a scientifically
recognised, publicly accessible registry maintained by government agencies or agencies authorised by the
government and that,
b) By way of such registration, the requirements set forth in no. 1 of para 2 of section 4 above have been
complied with.
3) The competent agency shall immediately acknowledge in writing receipt of the application and the attached
documents. At the same time, the agency shall request the opinion of the Central Ethics Commission on Stem
Cell Research. On receipt of the opinion, the agency shall notify the applicant of the content and the date of the
opinion adopted by the Central Ethics Commission on Stem Cell Research.
4) Approval shall be given if:
1. The requirements set forth in para 2 of section 4 above have been complied with,
2. The requirements set forth in section 5 above have been complied with and, accordingly, the research
project is ethically acceptable, and if
3. An opinion by the Central Ethics Commission on Stem Cell Research has been submitted following a
request by the competent agency to this effect.
5) If the application, complete with documentation, and the opinion of the Central Ethics Commission on Stem
Cell Research have been received, the agency shall decide in writing on the application within a period of two
months. In doing so, the agency shall consider the opinion adopted by the Central Ethics Commission Stem Cell
Research, the agency shall give its reasons in writing.
6) Approval can be limited in time or by imposing obligations to the extent necessary for complying with or
continuing to meet the approval requirements pursuant to para 4 above. If, following approval, events occur
which conflict with the granting of approval, approval can be withdrawn wholly or in part with effect in the
future or be limited in time or be made dependent on the fulfilment of conditions to the extent necessary for
complying with or continuing to meet the approval requirements set forth in para 4 above. Any objection to or
action for rescission of withdrawal or revocation of approval shall not suspend the effect of the decision.
The first authorisation to import human embryonic stem cell lines was given in December
2002.
3. Prohibition of the procurement of embryonic stem cells from human supernumerary
embryos.
Austria
The Austrian Reproductive Medicine Act of 1992 states that cells capable of development
may only be used for medical assisted reproduction. According to the interpretation of the
Reproductive Medicine Act the procurement of stem cells from embryonic tissues is
prohibited. The use of imported human ES cells is not explicitly prohibited and discussion
regarding authorisation is still ongoing.
Denmark
The Act on Medically Assisted Procreation from 1997 only allows research intending to
improve in vitro fertilisation technique or pre-implantation diagnosis techniques. Therefore,
the isolation of human ES cells from supernumerary embryos is forbidden. The importation of
40
human ES cells is not explicitly forbidden. However, the Danish government will give its
opinion on human embryonic stem cell research in spring 2003, and has recommended that no
research with human ES cell lines should be commenced until the government has presented
its decision to Parliament (See also chapter 3.3)
France
Under the Bioethics Law of 1994, research on human embryos in vitro is forbidden except for
research which does not harm the embryo. The import and use of human ES cell lines derived
from supernumerary embryos is not explicitly prohibited but the authorisation is still under
discussion. A revision of the Bioethics law is under discussion (see chapter 3.3)
Ireland
There is no legislation dealing with research on embryos. However, the Irish constitution of
1937 (as amended in 1983) provides that “the State acknowledges the right to life of the
unborn and, with due regard to the equal right to life of the mother, guarantees in its laws to
respect, and, as far as practicable, by its laws to defend and vindicate that right”.
Spain
The laws of 1988 on Assisted Reproduction Techniques and on donation and use of embryos
and foetuses or their cells authorises research on in vitro human embryos biologically nonviable under certain conditions. There is no clear interpretation of the concept of a non-viable
embryo. Concerning viable human embryos, only research for the benefit of the concerned
embryos is allowed. A revision of the law is under discussion (see chapter 3.3)
4. No specific legislation regarding human embryo research
Belgium
The Royal decree of 1999 fixes the requirement for in vitro fertilisation centres. There is no
specific legislation on research but the current practice is that research must only be
performed at in vitro fertilisation centres following approval from the local ethics committees.
A new bill is under discussion (see chapter 3.3).
Italy
Italy has not enacted legislation.
The Italian National Bioethics Committee has adopted an advice on “the therapeutic use of
stem cells”. A majority of the members considered the research on human supernumerary
embryos for the derivation of human ES cells as legitimate.
Luxembourg
There is no legislation covering human embryo research.
Portugal
Portugal has not enacted legislation but has ratified the Convention of the Council of Europe
on Human Rights and Biomedicine signed in Oviedo on 4 April 1997, which prohibit the
creation of human embryos for research purposes and has in addition the protocol on the
prohibition of human cloning. The National Council of Ethics has adopted opinions covering
these questions. It has taken the position that research with no benefit for the embryo
concerned is not legitimated. The Ministry of Science has created in 2002 a Steering
41
Committee for the preparation of a law on research on human embryos including human ES
cells.
5. Allowing for the creation of human embryos for stem cell procurement by law
UK is for the moment the only Member State with a specific law that permits the creation of
human embryos by fertilisation of an egg with a sperm or by somatic cell nuclear transfer.
The 1990 Act and the 2001 Regulation (see above) allow for the isolation of stem cells for
any of the 8 research purposes set out in the law.
The Dutch Embryo Act of 2002 announces, as a general principle, the prohibition of the
creation of human embryos solely for research purposes. However, this ban is not irreversible
and could be lifted by Royal Decree within five years after the coming into force of the Act.
6. Prohibition of the creation of human embryos for research purposes and for the
procurement of stem cells by law or by ratification of the Convention of the Council of
Europe on Human rights and Biomedicine signed in Oviedo on 4 April 1997
The creation of human embryos for research purposes and for the procurement of embryonic
stem cells is for the moment prohibited in Austria, Denmark, Finland, France, Germany,
Greece, Ireland, Netherlands, Portugal and Spain.
42
43
New regulations under discussion in EU Member States57
3.3.
Belgium
A bill on research on human embryos in vitro was approved by the Belgian Senate in 2002
and is now under discussion in the Parliament. The draft legislation proposes to authorise the
procurement of embryonic stem cells from supernumerary embryos under certain conditions
and the creation of a “Federal Commission for scientific medical research on embryos in
vitro”.
The bill also foresees to allow for the creation of human embryos for research purposes
including by means of somatic cell nuclear transfer.
Article 3 proposes to allow research on human embryos in vitro under the following
conditions:
–
–
–
–
–
–
research for therapeutic purposes
based on recent scientific knowledge
carried by a registered laboratory
embryos up to 14 days of development
no alternative method of research as effective
the consent of the donors
In addition the research is controlled at the local and federal levels.
Denmark
A revision of the current legislation to allow for the procurement of human ES cells from
supernumerary embryos is under discussion.
France
A revision of the Bioethics Law of 1994 has been approved by the Senate in January 2003
and should be discussed by the Parliament in the first semester of 2003. It proposes to allow
for research on supernumerary human embryos including the procurement of human ES cells
for 5 years under certain conditions. A central authorising body will be created.
The proposed revision of the Bioethics law (as amended by the Senate in January 2003)
prohibits human embryo research but includes a derogation for five years allowing for
research on supernumerary human embryos including the procurement of human ES cells
under the following conditions:
–
the research should have the potential to lead to major therapeutic advances and only
be undertaken if there is no alternative method of comparable effectiveness available;
–
the embryos must derive from an in vitro fertilisation, in the context of a medically
assisted reproduction (supernumerary embryos);
–
written consent of the couple from which the embryos are issued;
–
authorisation by a central body to be created.
The proposed bill will also allow the import of foetal or embryonic cells or tissues after prior
authorisation by the central body.
57
European Commission, DG Research, Directorate E: Survey on opinions from National Ethics
Committees or similar bodies, public debate and national legislation in relation to human embryonic
stem cell research and use (last update March 2003).
44
Italy
A law on in vitro fertilisation is under discussion. The Ministry of Health recently produced a
report about the banks conserving embryos and gametes.
Portugal
A committee has been established in Portugal for the preparation of a law on human embryo
and human ES cell research.
Spain
A revision of the current legislation is under discussion.
In 1998 the National Committee for Human Artificial Reproduction was created. In its second
opinion, delivered in 2002, it advised to conduct human embryonic stem cell research using as
a source supernumerary embryos, estimated in Spain to be over 30 000.
The Ethics Advisory Committee for Scientific and Technological Research was established in
April 2002 and gave in February 2003 its first opinion on research on stem cells. It
recommended to the government that research on both adult and embryonic stem cells should
be implemented; that the legislation should be modified to allow the isolation of human
embryonic stem cells from supernumerary embryos under the following condition: The
parents´ informed consent or, if this is not possible, the permission of the Centre of
Assisted Reproduction in charge of keeping the embryos according to the regulation in
force. The investigation must have the aim of alleviating human suffering and not just
economic ends. It must be exclusively done by working groups with a proved experience
in this field. The protocol of investigation must be previously evaluated by Ethics
Committees and it must be under their exhaustive control. Therefore, the control and
supervision of these investigations by a national committee is recommended.
Sweden
A revision of the current legislation is under discussion.
The Parliamentary Committee on Genetic Integrity proposed, in their report published 29
January 2003, not to implement a general prohibition against producing fertilised eggs for
research purposes. It is the opinion of the Committee that such production must take place in
order for research to be carried out on infertility and the development of the fertilised egg etc.
It is not possible to set a legal limit with sufficient clarity that would delineate what, on the
contrary, would be forbidden. This delineation should rather be done on a case-by-case basis
within the framework of ethics review of research. It should also be noted, however, that in
the view of the Committee the creation of embryos by transfer of somatic cell nuclei (socalled therapeutic cloning) should be treated in the same way and thus in principle be allowed.
45
3.4.
Regulations in some non-EU countries regarding human embryonic stem cell
research 58
Countries acceding to the EU:
Cyprus, Czech Republic, Estonia, Hungary, Lithuania, Slovak Republic, Slovenia have
ratified the Convention of the Council of Europe on biomedicine and human rights59.
No specific regulations regarding human embryonic stem cell research have a present been
implemented in the countries acceding to the EU.
Cyprus:
Cyprus has ratified the Convention of the Council of Europe on biomedicine and human
rights. There is no specific regulation regarding human embryo research.
Czech Republic:
Czech Republic has ratified the Convention of the Council of Europe on biomedicine and
human rights. There is no specific regulation regarding human embryo research, but a law is
under preparation.
Estonia
Under the Embryo Protection and Artificial Fertilisation Act of 1997 the use of
supernumerary human embryos for scientific research is permitted if informed consent has
been obtained.
Hungary
Under the Act of 1997 on Health Care (Chapter IX), research on human embryos is permitted
if these are supernumerary embryos and not older than 14 days. This research should be
approved by the Committee for Human Reproduction.
Latvia
In January 2002, Latvia has adopted a Law on Reproductive and Sexual Health. Research on
human embryos may be authorised if the conditions are met: absence of alternative method,
positive assessment of the scientific merit and ethical acceptability by an authorised body and
informed consent of the donors.
Lithuania
The Law on biomedical research adopted in 2000, allows only observational studies of human
embryos.
Malta
There is no specific regulation regarding human embryo research.
58
59
European Commission, DG Research, Directorate E: Survey on opinions from National Ethics
Committees or similar bodies, public debate and national legislation in relation to human embryonic
stem cell research and use (last update March 2003); “Candidate Countries legislation related to ethical
issues in science and research” Proceedings of the workshop of 8-10 December 2002 - Brussels organised by the European Commission - DG Research - Unit C3 - Ethics and Science"; “Use of
embryonic stem cells for therapeutic research”– Report of International Bioethics Committee –
UNESCO – 6 April 2001.
http://conventions.coe.int/treaty/en/treaties/html/164.htm
46
Poland
Under the Physician profession’s Act of 1996, human embryos may not be use for nontherapeutic research.
Slovak Republic
The Slovak Republic’s signing and ratifying the Convention on Human Rights and
Biomedicine and the Additional Protocol on the Prohibition of Cloning of the Human Beings,
already implemented in the national legislation, together with the older provisions contained
in law No. 277/1994 on health care, especially the prohibition of the “non-therapeutic
research” to be performed on human embryos and foetuses, were interpreted recently as
effectively banning all human cloning (the so-called “reproductive” as well as “therapeutic”).
There is a government proposal to amend the Slovak Republic’s Penal Code accordingly - i.e.
making human cloning a penal offence in the Slovak Republic (relevant wording being taken
basically from the Protocol, and the legislature implementing it in the Slovak Republic).
Slovenia
The law on medically assisted reproduction prohibits the creation of embryos for research
purposes and cloning of embryos and the use of in vitro fertilization for any purpose other
than the birth of a child. The Law on Medically assisted reproduction imposes strict
conditions for the use of supernumerary embryos in research. Research can be performed on
embryos that are not suitable for reproduction or storage, or on those at the end of the storage
period which would be destroyed. Embryos should not be older than 14 days.
The authorization of the National Medical Ethics committee should be obtained.
Other countries:
In Canada and USA there is no federal law regulating research on human embryos and/or the
derivation of human embryonic stem cells. The House of Commons in Canada is discussing a
draft law, which would regulate such research and allow for the procurement of human ES
cells from supernumerary embryos.
On 9 August, 2001, the President of the United States announced60 his decision to allow
Federal funds to be used for research on existing human embryonic stem cell lines as long as
prior to his announcement (1) the derivation process (which commences with the removal of
the inner cell mass from the blastocyst) had already been initiated and (2) the embryo from
which the stem cell lines was derived no longer had the possibility of development as a
human being.
In addition, the President established the following criteria that must be met:
–
–
–
–
The stem cells must have been derived from an embryo that was created for
reproductive purposes;
The embryo was no longer needed for these purposes;
Informed consent must have been obtained for the donation of the embryo;
No financial inducements were provided for donation.
The National Institutes of Health have implemented the above rules by setting a strategic
vision for research using stem cells, including:
60
http://escr.nih.gov/eligibilitycriteria.html
47
–
Creation of the Human Embryonic Stem cells Registry, which list the human
embryonic stem cells that meet the eligibility criteria,
–
Promoting the number of researchers with expertise in stem cell research. The NIH
recognised this as one of the key factors to allow stem cell research to move forward
and is currently soliciting grant applications to support training courses to teach
researchers how best to grow existing banked stem cells into useful lines.
–
A number of initiatives to facilitate research on all types of stem cells. In particular,
the NIH continues to support research on developing the therapeutic potential of
adult stem cells.
New federal legislation is under debate in the US Congress. The State of California has
passed a law, in September 2002, allowing the procurement of human embryonic stem cells
from supernumerary embryos. New legislation authorising the procurement of human ES cells
from supernumerary embryos is under discussion in the States of New Jersey and
Massachusetts.
In Australia a new law is under discussion to allow for the derivation of human ES cells from
supernumerary embryos.
Laboratories in Singapore, Taiwan, South Korea, China… are actively conducting human ES
cell research. Legislation regarding this research is under discussion in some of these
countries.
Annex D provides further information regarding provisions in non-EU countries relating to
human embryonic stem cell research.
3.5.
Governance of stem cell research in the context of FP6
As stated in the Treaty of the European Union, article 6:
“1. The Union is founded on the principles of liberty, democracy, respect for human rights
and fundamental freedom, and the rule of law, principles which are common to the Member
States.
2. The Union shall respect fundamental rights, as guaranteed by the European Convention for
the protection of Human Rights and Fundamental Freedoms signed in Rome on 4 November
1950 and as they result from the constitutional traditions common to the Member States, as
general principles of Community law.
3. The Union shall respect the national identities of its Member States.
4. The Union shall provide itself with the means necessary to attain its objectives and carry
through its policies.”
In accordance with the EU Treaty, each Member State retains its full prerogative to legislate
on ethical matters. At the level of the Community, ethical principles have been defined with
regard to the funding of research under the research Framework Programme.
As far as FP6 is concerned, the following ethical principles have been established:
The decision No. 1513/2002/EC of the European Parliament and of the Council of 27 June
2002 concerning the sixth framework programme of the European Community for research,
48
technological development and demonstration activities, contributing to the creation of the
European Research Area and to innovation (2002 to 2006) stipulates among others that61:
–
“Fundamental ethical principles are to be respected. These include the principles
reflected in the Charter of fundamental rights of the EU including the protection of
human dignity and human life…”
The Charter of Fundamental Rights of the European Union, proclaimed in Nice, France, on 7
December 2000, explicitly prohibits eugenic practices and reproductive cloning, but does not
comment explicitly on embryo research (article 3)
–
… “in accordance with relevant international conventions and codes of conduct, e.g.
… the Convention of the Council of Europe on Human Rights and Biomedicine
signed in Oviedo on 4 April 1997, and the Additional Protocol on the Prohibition of
Cloning Human Beings signed in Paris on 12 January 1998”
The Council of Europe’s Convention for the Protection of Human Rights and Dignity of the
Human Being with regard to the Application of Biology and Medicine of 199762 does not
resolve the matter of the permissibility of embryo research and leaves every country
responsibility for legislating on this matter, while stipulating two conditions: the prohibition
of producing human embryos for research purposes and the adoption of rules designed to
assure adequate protection for the embryo 63. An Additional Protocol to the Convention on the
Prohibition of Cloning Human Beings was approved in 1998 and took effect on 3 January
2001 in thirteen Member States of the Council of Europe64.
–
“… in accordance with Community law”
Some EU Directives are relevant for human ES cell research. For instance, the Directive
2001/20/EC on the approximation of laws, regulations and administrative provisions of the
Member States relating to the implementation of good clinical practice in the conduct of
clinical trials on medical products for human use establishes among others that “written
authorisation is required before commencing clinical trials involving medical products for
gene therapy, somatic cell therapy including xenogenic cell therapy and all medicinal
products containing genetically modified organisms” (ref. article 9.6). The Directive 98/44 on
the legal protection of biotechnological inventions, adopted on 6 July 1998, stipulates that
“processes for cloning human beings” and “uses of human embryos for industrial or
commercial purposes…shall be considered unpatentable”.
The draft Directive of the European Parliament and of the Council on setting standards of
quality and safety for the donation, procurement, testing, processing, storage, and distribution
of human tissues and cells is relevant in relation to the clinical use (including clinical trial) of
human ES cells and their derivatives.
–
“in accordance with legislation, regulations and ethical guidelines in countries where
the research will be carried out.”
61
OJ L232of 29.8.2002 p.4.
http://conventions.coe.int/treaty/en/treaties/html/164.htm
Fifteen countries have ratified the European Convention: Cyprus, Czech Republic, Denmark, Estonia,
Georgia, Greece, Hungary, Lithuania, Moldova, Portugal, Romania, San Marino, the Slovak Republic,
Slovenia and Spain.
Cyprus, Czech Republic, Estonia, Georgia, Greece, Hungary, Lithuania, Moldova, Portugal, Romania,
the Slovak Republic, Slovenia and Spain.
62
63
64
49
These ethical principles have been further specified in the Council decision of 30 September
2002 adopting a specific programme for research, technological development and
demonstration: “Integrating and strengthening the European Research Area” (2002-2006)65.
It is stated that:
–
The following fields of research shall not be financed under this programme:
–
research activities aiming at human cloning for reproductive purposes
–
research activity intended to modify the genetic heritage of human beings
which could make such change heritable 66
–
research activities intended to create human embryos solely for the purpose of
research or for the purpose of stem cell procurement, including by means of
somatic cell nuclear transfer (often referred to as therapeutic cloning).
–
In addition, funding of research activities that are prohibited in all the Member States
is in all circumstances excluded.
–
In compliance with the principle of subsidiarity and the diversity of approaches
existing in Europe, participants in research projects must conform to current
legislation, regulations and ethical rules in the countries where the research will be
carried out. In any case, national provisions apply and no research forbidden in any
given Member State will be supported by Community funding in that Member State.
–
Where appropriate, participants in research projects must seek the approval of the
relevant national or local ethics committees prior to the start of the RTD activities.
–
An ethical review will be implemented systematically by the Commission for proposals
dealing with ethically sensitive issues, in particular proposals involving the use of
human embryos and human embryonic stem cells.
Research proposals, which raise sensitive ethical concerns, undergo an ethical review at EC
level before funding. The proposals are reviewed by an independent, multidiciplinary and
transnational panel, which is established by the DG Research in relation to each call for
proposals. The review is conducted independently of the specific research programme and
separated from the scientific evaluation. The ethical review aims to ensure that the proposers
have identified all ethical issues, which the proposed research may raise, have taken the
appropriate measures to fulfil all ethical and/or legal requirements at national and European
level and finally have respected the ethical framework defined for the 6th Framework
programme for Research.
–
Any research involving the use of human embryos and human embryonic stem cells,
following the ethical review mentioned above, will be submitted to a Regulatory
Committee.
–
In specific cases, an ethical review may take place during the implementation of the
project.
65
OJ L294 of 29.10.2002, p. 8.
Research relating to cancer treatment of the gonads can be financed.
66
50
–
As stated in the Council minutes of 30 September 200267 “The Council and the
Commission agree that detailed implementing provisions concerning research
activities involving the use of human embryos and human embryonic stem
cells…shall be established by 31 December 2003”.
The Commission will during that period…not propose to fund such research, with the
exception of banked or isolated human embryonic stem cells in culture.
3.6.
Social scrutiny and dialogue
There are significant differences in national attitudes towards specific techniques and areas of
research. In particular, human embryonic stem cell research has recently provoked intense
public and political debate. As the life sciences and biotechnology develop, they contribute
considerably to securing welfare on the personal and societal levels as well as to creating new
opportunities for our economies. At the same time, the general public is increasingly
concerned about the social and ethical consequences of these advances in knowledge and
techniques as well as about the conditions forming the choices made in these fields.
The EGE stressed in its opinion regarding “Ethical aspects of human stem cell research and
use” there is a need for continuing dialogue and education to promote the participation of
citizens, including patients, in scientific governance, namely in social choices created by new
scientific developments”.
The need for public dialogue on scientific advances and new technologies has also been
highlighted in both the Commission’s communication on “Life Sciences and Biotechnology”,
published on 27 January 200268 and the Commission’s action plan on “Science and Society”
published in December 200169.
In this connection, the European Group on Life Sciences70, set up by the European Research
Commissioner Philippe Busquin, organised on 18-19 December 2001,a forum entitled “Stem
cells: therapies for the future?”. The aim was to offer a platform at European level for a
debate between, on one side, scientists and experts concerned with the feasibility and
consequences of stem cell research and, on the other side, a wide range of representatives of
society. More than 600 people participated in the event.71. Much of the public discussion that
took place, both at the forum itself and by e-mail exchanges concentrated on ethical issues,
particularly those relating to the use of human embryos.
As for any new potential treatment, the promises of stem cell research may create amongst
patients suffering from incurable diseases and their families, high and sometimes unrealistic
expectations from science and the imperative of treatment for whatever disease. Many
negative research results are not published and may lead to an unbalanced presentation in the
media and ultimately affect the dialogue in society. Since failure to deliver the promised cures
will have very negative impact on the perception of science by the public, it is vital to
communicate the state of the art and future possibilities in a most honest and realistic way.
The more science is able to keep its promises, the more it will receive the public recognition
necessary to reconcile the expansion of knowledge with social progress. There is a social role
67
68
69
70
71
Annex F.
http://europa.eu.int/comm/biotechnology
http://www.cordis.lu/science-society
http://europa.eu.int/comm/research/quality-of-life/genetics/en/13.html
http://europa.eu.int/comm/research/quality-of-life/stemcells.html
51
of the scientist and a responsibility on his/her side to communicate the advancement of
science in a meaningful way.
In the Commission’s Communication (COM(2003)96 final) on “Life Sciences and
Biotechnology – A strategy for Europe: Progress report and future orientations” published 5
March 2003 the Commission calls for initiatives that integrate discussion platforms as a
strategic element for research projects funded under FP6. The ethical and social debate should
be a natural part of the research and development process, involving society as much as
possible.
52
Chapter 4: Socio-economic aspects
4.
CHAPTER 4: S OCIO-ECONOMIC ASPECTS
Biotechnology is an area with strong potential economic growth and welfare creation. Stem
cell research plays a part in its development. Although considerable sums are available for
investment in stem cell research, commercial returns on such investments are for the moment
modest. This reflects the fact that most of this work is still at the basic research stage. Thus
commercial interests are trying to position themselves for profitability in the future, but still
face uncertain research prospects, therapeutic possibilities and the development of a
regulatory environment, the latter largely influenced by ethical issues and public concerns.
Regarding the exploitation of results of the stem cell research, many of the collaborations in
this area with industry involve small, dedicated firms rather than large pharmaceutical
companies. Small firms appear to play a key role in transferring technology from the science
base into industry. A number of start-up companies have been created as spin-offs from
academia in the sector.
In 2001 about 30 public and private biotechnology firms were doing stem cells research and
about a dozen are currently investigating the potential of both somatic and embryonic stem
cells. Few, if any, companies are investing solely in human embryonic stem cell research.
According to the Gilder Biotech report June 2001 the venture capital community is at present
giving preference to human somatic stem cells, which are reported to be closer to therapeutic
application than human embryonic stem cells72.
The companies are concerned with the use of stem cells including human embryonic stem
cells for:
–
Novel stem cell based therapies: direct stem cell transplantation, transplantation of
stem cell derived differentiated cells, stimulation of the body’s own stem cells via
e.g. growth factors or stem cells in gene therapy.
–
Drug discovery: use of stem cells for drug screening
–
Services and technologies: screening, isolation of stem cells, preparation and large
scale culture of stem cells, storage of stem cells.
One of the current framework conditions affecting stem cell research and commercialisation
of stem cells therapies is the patenting of human ES cells and their derivatives. On the one
hand patent rights are necessary to protect and secure industry’s huge investments to support
innovative research and development. On the other hand academic research is stimulated by
having free and open access to these cell lines, as they are essential starting materials for their
research. Some scientists consider that human embryonic stem cell lines should not be
patented at all. The debate on this issue is intense and includes the ethical dimension of this
72
Gilder Biotech report, The American Spectator, June 2001, “Adult cells do it better”;
http://www.gilderbiotech.com/ArticlesByScott/Op%20Ed/AdultCells.htm
53
research. The European Group on Ethics73 in Science and New Technologies (EGE)
recommended in their opinion No.16 on patenting of human stem cells that:
Isolated stem cells, which have not been modified do not, as product, fulfil the legal
requirements, especially with regards to industrial applications, to be seen as patentable. In
addition, such isolated cells are so close to the human body, to the foetus or to the embryo
they have been isolated from, that their patenting may be considered as a form of
commercialisation of the human body.
When unmodified stem cell lines are established, they can hardly be considered as a
patentable product. Such unmodified stem cell lines do not have indeed a specific use but a
very large range of potential undescribed uses. Therefore, to patent such unmodified stem cell
lines would also lead to too broad patents.
Therefore only stem cell lines which have been modified by in vitro treatments or genetically
modified so that they have acquired characteristics for specific industrial application, fulfil
the legal requirements for patentability.
As to the patentability of processes involving human stem cells, whatever their source, there is
no specific ethical obstacle, in so far as they fulfil the requirements of patentability (novelty,
inventive step and industrial application).
Directive 98/44 on the legal protection of biotechnological inventions, adopted on 6 July
1998, establishes that an element isolated from the human body or otherwise produced by
means of a technical process, including the sequence or partial sequence of a gene, may
constitute a patentable invention, even if the structure of that element is identical to that of a
natural element. Furthermore, the directive obliges Member States to consider unpatentable
inventions where their commercial exploitation would be contrary to order public or morality.
The processes for cloning human beings and uses of human embryos for industrial or
commercial purposes are in particular excluded from patentability.
The Commission published on 7 October 2002, the first annual report (provided for in article
16c of this Directive) on the implications of patent law for biotechnology and genetic
engineering. The report raised the issue related to patentability of human stem cells and cells
lines obtained from them.
In view of the preparation of future reports provided for in Article 16c of the directive the
Commission has set up a group of eminent experts from science, law, and economics, and
representatives from the European Patent Office (EPO) and the World Intellectual Property
Organisation (WIPO). The group’s mandate is to analyse important issues surrounding
biotechnological inventions. It will not touch upon ethical issues, which are the mandate of
the European Group on Ethics, but will focus more on legal and technical aspects and on the
mutual impact of the legal framework and the research and innovation area. In this light, one
of the issues identified and which will be further discussed by the expert committee will be
the patentability of human stem cells and cell lines derived from them.
The “16c expert group” will meet in May 2003 to discuss patenting of products and methods
involving human embryonic stem cell and human ES derivatives. The report of the 16c expert
group will be published at the same time as the 2003 annual monitoring report of the
Commission is delivered, towards the end of the year.
73
http://europa.eu.int/comm/european_group_ethics/docs/avis16_en.pdf
54
While many of the demonstrations of the potential of stem cell research have arisen from
academia, the development of this potential i.e. into therapeutic products requires industrial
and commercial inputs. For example, industrial involvement will be needed for large scale
and good manufacturing production of cell lines, to support multicentre clinical trials,
marketing, distribution etc.
55
GLOSSARY
GLOSSARY
Adult stem cell: a stem cell derived from the tissues or organs of an organism after birth (in
contrast to embryonic or foetal stem cells)
Blastocyst: a hollow ball of 50-100 cells reached after about 5 days embryonic development.
The blastocyst consists of a sphere made up of an outer layer of cells (the trophectoderm), a
fluid-filled cavity (the blastocoel), and a cluster of cells on the interior (the inner cell mass)
Cell culture: growth of cells in vitro on an artificial environment
Cell line: cells of common descent continuously cultured in the laboratory is referred to as a
cell line
Chromosomes: the carrier of genes, the hereditary information which resides in DNA
Clone: a cell or organism derived from and genetically identical to another cell or organism
Cloning: creating an organism that is genetically identical to another organism, or a cell that
is genetically identical to another cell provided that the so-called mother and daughter cells
are subsequently separated (see also reproductive and therapeutic cloning)
Cloning by somatic cell nuclear transfer: involves replacing an egg’s nucleus with the
nucleus of the adult cell to be cloned (or from an embryo or foetus) and then activating the
egg’s further development without fertilisation. The egg genetically reprogrammes the
transferred nucleus, enabling it to direct development of a whole new organism
(Reproductive cloning by cell nuclear transfer).
OR the development is stopped at the blastocyst stage and embryonic stem cells are derived
from the inner cell mass. These stem cells would be differentiated into desired tissue using a
cocktail of various growth and differentiation factors. The generated tissue/cells could then be
transplanted into the original donor of the nucleus avoiding rejection (Therapeutic cloning
by cell nuclear transfer).
Culture medium: the broth that covers cells in a culture dish, which contains nutrients to
feed the cells as well as other growth factors that may be added to direct desired changes in
the cells
Dedifferentiation: the process of inducing a specialised cell to revert towards less
differentiated cell.
Differentiation: the process whereby an unspecialized cell acquires the features of a
specialised cell such as a heart, liver, or muscle cell.
DNA: deoxyribonucleic acid, the genetic material; it is composed of long double stranded
chains of nucleotides, the basis of genetics
Embryo: in humans, the developing organism from the time of fertilization until the end of
the eighth week of gestation, when it becomes known as a foetus.
56
Early embryo: the term “early embryos” covers stages of the development up to the
appearance of the primitive streak e. g. until 14 days after fertilisation.
Embryonic germ cell: embryonic germ cells are isolated from the primordial germ cells of
the gonadal ridge of the 5-10 weeks foetus.
Embryonic stem cell line: embryonic stem cells, which have been cultured under in vitro
conditions that allow proliferation without differentiation for months to years
Feeder layer: cells used in co-culture to maintain pluripotent stem cells
Fertilization: the process whereby male and female gametes unite
Foetus: a developing human from eight weeks after conception to birth
Foetal stem cell: a stem cell derived from foetal tissue (in biological terms « embryo » covers
all stages of development up to eight weeks of pregnancy, from then on the term « foetus » is
used). A distinction is drawn between the foetal germ cells, from which the gametes develop,
and the remaining foetal stem cells, which are the foetal somatic cells
Gamete: the male sperm or female egg
Gene: a functional unit of heredity that is a segment of DNA located in a specific site on a
chromosome. A gene directs the formation of an enzyme or other protein.
Germ cells: ova and sperm, and their precursors
Haematopoïetic stem cell: a stem cell from which all red and white blood cells develop
Human embryonic stem cell: pluripotent stem cell derived from the inner cell mass of the
blastocyst
Implantation: the embedding of a blastocyst in the wall of the uterus. In humans
implantation takes place at day 8 after fertilization.
In vitro and in vivo: outside and inside the body; in vitro (literally, in glass) generally means
in the laboratory
In vitro fertilization: the fertilization of an egg by a sperm outside the body
Multipotent: Multipotent stem cells are those capable to give rise to several different types of
specialised cells constituting a specific tissue or organ.
Oocyte: the female egg
Plasticity: the ability of stem cells from one tissue to generate the differentiated cell types of
another tissue
Pluripotent stem cell: a single pluripotent stem cell has the ability to give rise to types of
cells that develop from the three germ layers (mesoderm, endoderm and ectoderm) from
which all the cells of the body arise. Pluripotent stem cells have the potential to generate into
every cell type in the body, but cannot develop into a embryo on their own.
57
Pre-implantation embryo: is an embryo in the stage prior to implantation in the wall of the
uterus ; an embryo cannot develop beyond the blastocyst stage without implantation into the
womb.
Primitive streak: a collection of cells which appears at about 14 days after fertilisation from
which the heart, blood and the central nervous system develops
Proliferation: expansion of a population of cells by the continuous division of single cells
into two identical daughter cells
Redifferentiation: the process of inducing a dedifferentiated cell to differentiate into a
(different) specialised cell type
Somatic cell: cell of the body other than egg or sperm
Somatic stem cell: an undifferentiated cell found among differentiated cells in a tissue or
organ, which can renew itself and can differentiate to yield the major specialised cell types of
the tissue or organ.
Somatic cell nuclear transfer: the transfer of a cell nucleus to an egg (or another cell) from
which the nucleus has been removed..
Supernumerary embryo or spare embryo: an embryo created by means of in vitro
fertilisation (IVF) for the purpose of assisted reproduction but subsequently not used for it.
Totipotent: At two to three days after fertilisation, an embryo consists of identical cells,
which are totipotent. That is to say that each could give rise to an embryo on its own
producing for example identical twins or quadruplets. They are totally unspecialised and have
the capacity to differentiate into any of the cells which will constitute the foetus as well as the
placenta and membranes around the foetus.
Transdifferentiation: the observation that stem cells from one tissue may be able to
differentiate into cells of another tissue
Undifferentiated: not having changed to become a specialized cell type
58
ANNEXES
59
ANNEX A: Biology of human development
ANNEX A: BIOLOGY OF HUMAN DEVELOPMENT
The development of the embryo is a continual process of change, which can be described in
terms of the following seven stages:
1. Day 0: Fertilisation
The female egg (“oocyte”) is fertilised by the male sperm. The egg and sperm each carry half
the genes of a normal cell. The process of fertilisation consists of a number of steps, which
ultimately result in a single cell, the “zygote”. The zygote contains all the genes necessary for
the development of an individual, half derived from the mother and half from the father. A
very small proportion of genes is contained in the mitochondria and is inherited exclusively
from the mother.
2. Day 3-4:
Up to the fourth cell stage at day 3-4 all the cells are essentially identical and all are thought
to have the potential, if placed in the right environment, to develop into an individual – the
cells are “ totipotent” (i.e. they have the capacity to develop into all type of cells needed for
human development including the extra-embryonic tissues such as the placenta and the
umbilical cord). Indeed, identical twins can result from the splitting of the cells at this early
stage: they are genetically identical as a result of developing from the same fertilised egg
(identical twins can arise later i.e. up to 14 days).
3. Days 4-5: Morula Stage
At four to five days after fertilisation (morula stage), the embryo is still made up of
unspecialised embryonic cells, but theses seems no longer to have the potential to give raise to
an embryo on their own.
4. Days 5-7: Blastocyst stage
At day 5 after fertilisation the cells constituting the embryo start to differentiate into inner and
outer cells. The outer cells go on to develop into non-embryonic tissues such as the placenta
or umbilical cord. The inner cell mass will give rise to the embryo itself. If these inner cells
are isolated and grown in the presence of certain chemical substances (growth factors),
pluripotent embryonic stem cells (ES cells) can be derived. The ES cells, which have the
potential to generate into the various cell type in the body (more than 200 types are known),
are referred to as “ pluripotent”.
A pre-implantation embryo is an embryo in the stage prior to implantation in the wall of the
uterus; an embryo cannot develop beyond the blastocyst stage without implantation into the
uterus.
5. Day 8: Implantation stage
About day 8 after fertilisation implantation of the blastocyst in the womb takes place. If
implantation does not take place, the blastocyst does not develop, as it will lack specific
60
biochemical signals and nutrients from the mother, which are required for further
development. A substantial proportion of the human embryos – many estimate it as high as 75
per cent – are naturally lost before implantation. At this stage the cells are still relatively
undifferentiated and there is no trace of human structure such as a nervous system.
6. Days 14-21: Gastrula stage
At about 14 days after fertilisation, following implantation, the early embryo consists of about
2000 cells. It is only at this stage that the cells begin to become differentiated into more
specialised cell types. The “primitive streak”, which gives rise to heart and blood, and from
which the central nervous system develops, begins to appear at day 15. By the end of the third
week of embryonic development the evolving organism consists of three different cell layers,
the ectoderm, mesoderm and endoderm. Each cell layer is “programmed” to give rise to
defined tissues and organs. The embryonic “outer” layer, or ectoderm, gives rise to the
following tissues: central nervous system (brain and spinal cord) and peripheral nervous
system; outer surface or skin of the organism; cornea and lens of the eye; epithelium that lines
the mouth and nasal cavities and the anal canal; epithelium of the pineal gland, pituitary
gland, and adrenal medulla; and cells of the neural crest (which gives rise to various facial
structures, pigmented skin cells called melanocytes, and dorsal root ganglia, clusters of nerve
cells along the spinal cord). The embryonic “middle” layer, or mesoderm, gives rise to
skeletal, smooth, and cardiac muscle; structures of the urogenital systems (kidneys, ureters,
gonads, and reproductive ducts); bone marrow and blood; fat; bone, and cartilage; other
connective tissues; and the lining of the body cavity. The embryonic “inner” layer, or
endoderm, gives rise to the epithelium of the entire digestive tract (excluding the mouth and
anal canal); epithelium of the respiratory tract; structures associated with the digestive tract
(liver and pancreas); thyroid, parathyroid, and thymus glands; epithelium of the reproductive
ducts and glands; epithelium of the urethra and bladder.
The term “early embryo” covers stages of development up to the appearance of the primitive
streak e.g. until 14 days after fertilisation.
7. Eight week after fertilisation: Foetal stage
After about seven weeks’ development, individual organs become recognisable and the
embryonic stage is finished and the embryo can properly be described as a foetus. A
distinction is drawn between the foetal germ cells from which the gametes (egg cells and
sperm) develop and from which “pluripotent” embryonic germ stem cells (EG cells) can be
derived during a brief period in the early foetal development and the remaining foetal tissue
from which “multipotent” foetal somatic stem cells can be derived.
8. Nine months after fertilisation: birth
At around nine months, given normal gestation, the baby is born.
61
ANNEX B: Possibilities to overcome immune rejection responses
in stem cell therapy
ANNEX B: POSSIBILITIES TO OVERCOME IMMUNE REJECTION
RESPONSES IN STEM CELL THERAPY
There are several ways of avoiding or repressing immune rejection of transplanted cells or
tissues74:
1) Use of immune-suppressant drugs
These drugs, which suppress the activity of the immune system, have been refined over many
years, as part of organ transplantation research. However, they are not always effective; they
must normally be taken over the lifetime of the patient; and they leave the patient open to
infection.
2) Use of “matching” tissues
The magnitude of rejection is dependent on the differences between the patients HLA system
and that of the donor. For this reason, the differences should be as small as possible.
Sometimes during transplantation it is possible to get a matched tissue type, usually from a
near relative. This is often sought for bone marrow transplants. Finding a matching donor is
unlikely to be a useful approach for most cell-based therapies. However, because stem cells
can, in principle, be cultured indefinitely, it might be possible to establish stem cell banks of
sufficient size to comprise stem cells with a reasonable (though never perfect) match to the
majority of individuals in the population. If this proved possible, the appropriate matching
stem cell from the bank could be selected and differentiated into the cell type required for
therapy. Several thousand stem cell lines would be needed to obtain matches to the majority
of the population comparable with those achieved with matched bone marrow transplants.
3) Generation of immunotolerance
Rejection can also be reduced by the generation of immunotolerance. Previous administration
of embryonic material, or haematopoietic cells from the stem cell donor, might cause the
patient’s immune system to become habituated to some extent and smaller doses of
immunosuppressive drugs would be required, or none at all. In addition, research is being
carried out into the possibility of preventing an immune reaction by enclosing the cells to be
transplanted in a capsule of inert material.
The brain is normally a privileged site for transplantation as the brain does not have an
immune system, which cause rejection. However, in many pathological situations the blood
brain barrier is compromised and therefore the brain may not be as immunoprivileged as
previously thought, because immune cells then can enter the brain from blood.
4) Using the individual’s own cells or tissues
This would be the surest means of avoiding immune rejection. Adult stem cells isolated from
an individual, and then used to treat him or her, offer one possible way of achieving this,
74
House of Lords Select Committee “Report on Stem cell research” http://www.parliament.the-stationeryoffice.co.uk/pa/ld200102/ldselect/ldstem/83/8301.htm; The Health Council of the Netherlands’ report
on “Stem cells for tissue repair. Research on therapy using somatic and embryonic stem cells”, June
2002. http://www.gr.nl/pdf.php?ID=429.
62
although not in all circumstances. Alternatively somatic cell nuclear transfer (to egg cells or
human ES cells in culture) could be used to generate cells or tissues that match those of the
patient.
63
ANNEX C: Examples of available human embryonic stem cell
lines
ANNEX C: EXAMPLES OF AVAILABLE HUMAN EMBRYONIC STEM
CELL LINES
Sweden:
Karolinska Institute:
The US National Institutes of Health (NIH) register 75 contained initially six human ES cell
lines from the Karolinska Institute in Stockholm. However, these cell lines are currently not
available. The six cell lines have been frozen and the work on thawing, expanding and
characterising have now started. Two of these human ES cell lines have been grown on mouse
feeder layer. The remaining four preparations were frozen at an earlier stage. However, these
four preparations were established using human feeder cells, not mouse cells, and they are
therefore very valuable for the future. It is expected that the initial NIH lines thawed should
be available for others researchers within the next 12 months.
In addition to these original lines, there are at present three other stem cell lines in culture.
One is fully characterised and has been expanded to such a degree that this is now being
supplied to various groups for collaborative studies. The characterisation of the other two
lines is expected to be completed shortly. A cell bank will be established, based on the various
stem cell lines established at Karolinska Institute, and these will be available for other
scientists76.
Sahlgrenska Academy, Gothenburg University in collaboration with Cell Therapeutics
Scandinavia, AB:
21 human ES cell lines have so far been established. Four of these have been fully
characterized and two of these four fulfil all the criteria for self-renewal and pluripotency of
human ES cells. The remaining 17 cell lines have been partially characterized77.
Israel:
Six human embryonic stem cell lines have been established and characterised at the Rambam
Medical Center, Technion- Israel Institute of Technology. Four cell lines are available and
have been registrated at the NIH registry. The institute has also cell lines initially produced at
the Wisconsin. These cell lines are available for collaborative studies 78.
Australia:
The Australian Senate passed the Research Involving Human Embryos Bill on 5 December,
2002 allowing the destruction of human embryos for research purposes including the
procurement of embryonic stem cells from supernumerary embryos. The legislation, pending
the decision of State and Territory Parliaments, is expected to take effect beginning of 2003.
75
76
77
78
http://escr.nih.gov/eligibilitycriteria.html
Communication from Professor Carlstedt - Duke, Dean of Research, Karolinska Institute, Sweden
Communication from Professor Hamberger, Goteborg University, Sweden.
Communication from Professor Itskovitz -Eldor, Rambam Medical Centre, Israel.
64
Among others researchers at the Monash Institute are expecting to start deriving new human
embryonic stem cell lines from supernumerary embryos however the stem cell lines will not
be available until 2004 79.
79
Communication from Professor Pera, Monash Institute, Australia.
65
ANNEX D: Details regarding provisions in non-EU countries
relating to human embryonic stem cell research
ANNEX D: DETAILS REGARDING PROVISIONS IN NON -EU
COUNTRIES RELATING TO HUMAN EMBRYONIC
STEM CELL RESEARCH
Examples of regulatory regimes in some countries associated to the 6th Framework
Programme for Research80
Iceland
The act of 1996 on Artificial Fertilisation regulates research on human embryos. The creation
of embryos for research is prohibited, as is cloning. Research on human supernumerary
embryos is allowed:
- if it is part of an in vitro fertilisation treatment,
- if the intention is to diagnose hereditary diseases in the embryos themselves,
- if the purpose is to advance the treatment of infertility, or
- if the purpose is to improve understanding of the causes of congenital diseases and
miscarriages.
Israel
The currently existing Public Health (Extra-Corporeal Fertilization) Regulations, 1997
address neither the question of the fate of frozen embryos at the end of the freezing period nor
the issue of supernumerary embryos (i.e. embryos initially formed in the course and for the
sake of infertility treatment and not replaced or donated for implantation for some bona fide
reason). Likewise, the currently proposed law for the regulation of the donation of eggs for
purposes of in vitro fertilization does not address the possibilities of embryo stem cell
research. In 1999, the Israel Parliament enacted the Prohibition of genetic intervention Act
1999-5759 (human cloning and genetic modification of reproductive cells). The law prohibits
specifically human reproductive cloning but does not relate to cloning for non-reproductive
purposes, such as ES cell derivation
The Bioethics Advisory Committee of the Israel National Academy of Sciences and
Humanities, adopted a recommendation on 8 August 2001 stating that it should be permissible
to donate human supernumerary embryos no longer destined to implantation for research
under certain conditions, such as:
- free and informed consent,
- no selling or buying of human embryos,
- no in vitro culturing of human embryos beyond 2 weeks.
80
European Commission, DG Research, Directorate E: Survey on opinions from National Ethics
Committees or similar bodies, public debate and national legislation in relation to human embryonic
stem cell research and use (last update March 2003)
66
- separation of the medical teams involved in the IVF treatment and in the stem cell research.
The Advisory Committee also considers it ethically permissible to experiment with new
technologies to produce ES cells such as nuclear transfer (so-called therapeutic cloning
without reproductive purpose).
The Advisory committee also recommends that the “National Helsinki committee for genetic
research in humans” of the Israel Ministry of Health examine the research protocols. In
November 2002, the National Helsinki Committee has accepted in principle to authorise
applications in the two above categories.
Norway
"A bill amending the Act no 56 of 5 August 1994 relating to the application of biotechnology
in medicine was assented by the King/sanctioned 13 December 2002. The amendments
became effective 1 January 2003 and clarify that the prohibition against research on human
embryos also includes research on stem cell lines created by isolating and culturing stem cells
from human embryos. The bill also laid down a ban on therapeutic cloning."
Switzerland
The Federal law on medically assisted reproduction of 18 December 1998 regulates research
on embryos. Research on existing embryos is forbidden as well as creation of embryos for
research purposes. The donation of embryos is forbidden by the Constitution (article 119).
At the end of May 2002, a draft of the Swiss "Federal Act on Research on Supernumerary
Embryos and Embryonic Stem Cells" (EFG, Embryonenforschungsgesetz/ Embryonic
Research Act) reached the pre-legislative consultation stage. The Federal Council
(government) handed over a proposal for the act to parliament end of November 2002. It is
the parliament’s aim to enact the law before end of 2003.
This draft law proposes to allow research on "surplus" embryos from in vitro fertilisation for
purposes of an important scientific interest in the context of reproductive medicine or
developmental biology [and not “any possible purpose”] up to the 14th day after fertilisation,
and the derivation of embryonic stem cells from supernumerary embryos for research
purposes. The EFG draft defines an embryo as "the developing organism from the point of
nuclear fusion until the completion of organ development". Interpreting the constitutional
paragraph that bans “all kinds of cloning” it explicitly forbids therapeutic cloning.
Examples of regulatory regimes in third countries
Australia
A new bill was voted by the Senate in 2002, which will authorize derivation of human ES
cells from supernumerary human embryos. The law may be voted by the House of
Representatives in early 2003.
Canada
No legislation is currently in place. A new draft law on assisted human reproduction is now in
discussion in the House of Commons and addresses the questions of research on human
embryos. It proposes to prohibit the creation of embryos for research purposes but would
allow research on supernumerary embryos including the procurement of human embryonic
stem cell from supernumerary embryos. It also requires the informed consent of the donor of
the gametes.
67
The Canadian Institute for Health has established guidelines concerning human stem cell
research. It allows the funding of the procurement of human embryonic stem cell from
supernumerary embryos.
India81
The National bioethics panel set up by the Indian Department of Biotechnology (Ministry of
Science and Technology) has drafted new guidelines for human genomics research that cover
the collection and use of human ES cells. The panel recommends that the embryos should not
be older than 14 days, both donors should give informed consent and all projects should be
approved by the National bioethics panel. The creation of embryos for research purposes
should not be undertaken. In the case of commercial exploitation, a sharing of profits with the
donors should be organized.
Japan
The Japanese Parliament enacted the “Human Cloning Regulation Act” on 30 November
2000. The act authorizes research on human embryos in vitro including the procurement of
human embryonic stem cells. The detailed implementation of the act is left to the
administrative guidelines.
Singapore82
Singapore's Bioethics Advisory Committee has recommended a complete ban on human
reproductive cloning and recommends that human stem cell research and therapeutic cloning
be permitted under strict regulation.
The regulatory framework should
- require the informed voluntary consent of donors,
- prohibit the commerce and sale of donated materials, especially supernumerary embryos and
- stipulate that no one shall be under a duty to participate in any manner of research on human
stem cells to which he has a conscientious objection.
The Government has announced that it will follow the recommendations of the Bioethics
Advisory Committee published on 21 June 2002. It is the responsibility of the Health Minister
to licence such research.
South Korea
The Government has annonced that that it will approve the use of less than 14 day-old
embryos for stem cell research. A new regulation will be submitted to the Korean National
Assembly.
USA
Only publicly funded research is regulated. On 9 August 2001, President Bush announced that
federal funds might be awarded for research using human embryonic stem cell lines that meet
certain criteria 83. Such research is now eligible for federal funding as long as the derivation
process (which begins with the destruction of the embryo) was initiated prior to 9 August
2001. These stem cells must have been derived from embryos created for reproductive
81
82
83
http://dbtindia.nic.in/consent.html
http://www.bioethics-singapore.org/bac/index.jsp
http://grants.nih.gov/grants/stem_cells.htm
68
purposes and no longer needed for those purposes. In addition, informed consent must have
been obtained for the donation of the embryo and the donation must not have involved
financial inducements. The NIH Human Embryonic Stem Cell Registry has been created and
is updated to reflect stem cell lines that meet the eligibility criteria (see also chapter 2.6).
There is no federal law regulating research on human embryos and the derivation of human
ES cells when such research is funded by the private sector.
However, California has passed a law, in September 2002, allowing the procurement of
human embryonic stem cells from supernumerary embryos. New legislation authorising the
procurement of human ES cells from supernumerary embryos is under discussion in the States
of New Jersey and Massachusetts.
69
ANNEX E: Opinion No.15 of the European Group on Ethics
regarding ethical aspects of human stem cell research and use
ANNEX E: OPINION NO.15 OF THE EUROPEAN GROUP ON ETHICS
REGARDING ETHICAL ASPECTS OF HUMAN STEM CELL
RESEARCH AND USE E - OPINION EGE
OPINION OF THE EUROPEAN GROUP ON ETHICS
IN SCIENCE AND NEW TECHNOLOGIES
No 15
14 November 2000
***************************************************************************************************************************
ETHICAL ASPECTS OF HUMAN STEM CELL RESEARCH AND USE
Reference:
Initiative of the Group
Rapporteurs:
Anne McLaren and Göran Hermerén
***************************************************************************************************************************
The European Group on Ethics in Science and New Technologies (EGE),
Having regard to the Treaty on European Union as amended by the Treaty of Amsterdam, and in
particular Article 6 (formerly Article F) of the common provisions, concerning the respect for fundamental
rights, Article 152 (formerly Article 129) of the EC Treaty on public health, (namely paragraph 4(a)
referring to substances of human origin) and Articles 163-173 (formerly Articles 130F-130P) on research
and technological development;
Having regard to the European Parliament and Council Directive 65/65/CEE of 26 January 1965 and the
modified Directive 75/319/CEE of 20 May 1975 concerning medicinal products;
Having regard to the Council Directive 93/42/EEC of 14 June 1993 concerning medical devices and the
European Parliament and Council Directive 98/79/EC of 27 October 1998 concerning in vitro diagnostic
medical devices, in particular Article 1-4 which refers to ethics and requires the respect of the principles
of the Convention of the Council of Europe on Human Rights and Biomedicine, with regard to the
removal, collection and use of tissues, cells and substances of human origin;
Having regard to the Council Directive 98/44/EC of 6 July 1998 on the legal protection of
biotechnological inventions and in particular Article 6, concerning certain inventions excluded from
patentability, and Article 7 giving mandate to the European Group on Ethics (EGE) to evaluate "all
ethical aspects of biotechnology”;
70
Having regard to the Parliament and Council Decision of 22 December 1998 concerning the 5th
Framework Programme of the European Community for research, technological development and
demonstration activities (1998-2002) and in particular Article 7 requesting compliance with fundamental
ethical principles;
Having regard to the Council Decision of 25 January 1999 adopting the specific programme for research,
technological development and demonstration activities on quality of life and management of living
resources and in particular the ethical requirements mentioned in its Annex II;
Having regard to the Charter of 28 September 2000 on Fundamental Rights of the European Union,
approved by the European Council in Biarritz on October 14th 2000, in particular Article 1 on “Human
dignity”, Article 3 on the “Right to the integrity of the person”, which refers to the principle of "free and
informed consent" and prohibits "the reproductive cloning of human beings" and Article 22 on “Cultural,
religious and linguistic diversity”;
Having regard to the Council of Europe’s Convention on Human Rights and Biomedicine, signed on 4
April 1997 in Oviedo, in particular Article 18 on embryo research, and to the additional protocol to the
Convention on the prohibition of cloning human beings signed on 12 January 1998 in Paris;
Having regard to the Universal Declaration on the Human Genome and Human Rights adopted by the
United Nations on 11 December 1998, in particular Article 11 which recommends to prohibit reproductive
cloning of human beings, and Article 13 which refers to the responsibilities of researchers as well as of
science policy makers;
Having regard to national regulations on stem cell and on embryo research and to national ethics bodies
opinions, at the European Union level, concerning these subjects;
Having regard to the reports of the US National Bioethics Advisory Committee dated September 13,
1999 on the "Ethical Issues on Human Stem Cell Research", the hearings on the same subject by the
US Congress, on April 2000 and the guidelines published by the Clinton administration on August 26,
2000 to be forwarded to a NIH (National Institutes of Health) scientific review in 2001;
Having regard to the Round Table organised by the Group on 26 June 2000 in Brussels with members of
the European Parliament, jurists, philosophers, scientists, representatives of industries, of religions, of
patients' associations, and of international organisations (Council of Europe, UNESCO, WHO);
Having regard to the Hearings of scientific experts on 6 June 2000 and on 2 October 2000, and to the
Hearings of representatives of religions on 8 September 2000;
Having heard the rapporteurs Anne McLaren and Goran Hermerén;
1-
WHEREAS
SCIENTIFIC BACKGROUND
1.1.
How to define stem cells?
Stem cells are cells that can divide to produce either cells like themselves (self-renewal), or cells of one or
several specific differentiated types. Stem cells are not yet fully differentiated and therefore can reconstitute one
or several types of tissues.
71
1.2.
What are the different kinds of stem cells?
Different kinds of stem cells can be distinguished according to their potential to differentiate. They are progenitor,
multipotent or pluripotent stem cells.
•
Progenitor stem cells are those whose terminally differentiated progeny consist of a single cell
type only. For instance, epidermal stem cells or spermatogonial stem cells can differentiate
respectively into only keratinocytes and spermatozoa.
•
Multipotent stem cells are those which can give rise to several terminally differentiated cell types
constituting a specific tissue or organ. Examples are skin stem cells which give rise to epidermal
cells, sebaceous glands and hair follicles or haematopoietic stem cells, which give rise to all the
diverse blood cells (erythrocytes, lymphocytes, antibody-producing cells and so on), and neural
stem cells, which give rise to all the cell types in the nervous system, including glia (sheath cells),
and the many different types of neurons.
•
Pluripotent stem cells are able to give rise to all different cell types in vitro. Nevertheless, they
cannot on their own form an embryo. Pluripotent stem cells, which are isolated from primordial
germ cells in the foetus, are called: embryonic germ cells ("EG cells"). Those stem cells which are
isolated from the inner cell mass of a blastocyst-stage embryo are called: embryonic stem cells ("ES
cells”).
It should be noted that scientists do not yet all agree on the terminology concerning these types of stem cells.
1.3.
What are the characteristics of the different stem cells?
Progenitor and multipotent stem cells may persist throughout life. In the foetus, these stem cells are
essential to the formation of tissues and organs. In the adult, they replenish tissues whose cells have a limited
life span, for instance skin stem cells, intestinal stem cells and haematopoietic stem cells. In the absence of stem
cells, our various tissues would wear out and we would die. They are more abundant in the foetus than in the
adult. For instance haematopoietic stem cells can be derived from adult bone marrow but they are particularly
abundant in umbilical cord blood.
Pluripotent stem cells do not occur naturally in the body, which distinguishes them from progenitor and
multipotent stem cells.
1.4.
Where can stem cells be found?
The possible sources of stem cells include adult, foetus and embryos. Accordingly, there are:
•
Adult stem cells: progenitor and multipotent stem cells are present in adults. Mammals appear to contain
some 20 major types of somatic stem cells that can generate liver, pancreas, bone and cartilage but they are
rather difficult to find and isolate. For instance, access to neural stem cells is limited since they are located in
the brain. Haematopoietic stem cells are present in the blood, but their harvesting requires stimulatory
treatment of the donor's bone marrow. By and large, adult stem cells are rare and do not have the same
developmental potential as embryonic or foetal stem cells.
•
Stem cells of foetal origin:
- Haematopoietic stem cells can be retrieved from the umbilical cord blood.
72
- Foetal tissue obtained after pregnancy termination can be used to derive multipotent stem cells like
neural stem cells which can be isolated from foetal neural tissue and multiplied in culture, though they
have a limited life span. Foetal tissue can also give rise to pluripotent EG cells isolated from the
primordial germ cells of the foetus.
•
Stem cells of embryonic origin: Pluripotent ES cells are those which are derived from an embryo at the
blastocyst stage. Embryos could be produced either by in vitro fertilisation (IVF) or by transfer of an adult
nucleus to an enucleated egg cell or oocyte (somatic cell nuclear transfer – SCNT).
1.5. Human embryonic development
•
At two to three days after fertilisation, an embryo consists of identical cells which are totipotent. That is to
say that each could give rise to an embryo on its own producing for example identical twins or quadruplets.
They are totally unspecialised and have the capacity to differentiate into any of the cells which will constitute
the foetus as well as the placenta and membranes around the foetus.
•
At four to five days after fertilisation (morula stage), the embryo is still made up of unspecialised
embryonic cells, but these cells can no longer give rise to an embryo on their own.
•
At five to seven days after fertilisation (blastocyst stage), a hollow appears in the centre of the morula,
and the cells constituting the embryo start to be differentiated into inner and outer cells:
- The outer cells will constitute the tissues around the foetus, including the placenta.
- The inner cells (20 to 30 cells) will give rise to the foetus itself as well as to some of the surrounding
tissues. If these inner cells are isolated and grown in the presence of certain chemical substances
(growth factors), pluripotent ES cells can be derived. ES cells are pluripotent, not totipotent since they
cannot develop into an embryo on their own. If they are transferred to a uterus, they would neither
implant nor develop into an embryo.
HISTORICAL BACKGROUND
1.6.
•
Research on animals
Embryonic stem cells
Scientists have been working with mouse embryonic stem cells in vitro for more than 20 years, noting very
early their remarkable capacity to divide. Some mouse ES cell lines have been cultured for more than 10
years, while retaining their ability to differentiate.
There is today some evidence from animal models that multipotent stem cells can be used for
somatic therapy. Convincing evidence however has been provided up until now from ES cell-derived, and
not adult derived multipotent somatic cells. For instance neural differentiated mouse ES cells when
transplanted into a rat spinal cord several days after a traumatic injury can reconstitute neuronal tissue
resulting in the (partial) recovery of hindlimb co-ordinated motility. Similarly, selected cardiomyocytes
obtained from differentiating ES cells can be grafted into the heart of dystrophic mice to effect myocardial
repair. Whether the same cellular derivatives when obtained from adult stem cells would be able to correct
for the deficiencies induced in those animal models remains to be determined.
Much research on mouse ES cells has also been focused on using these cells to create transgenic
animals, in particular as disease models to study human genetic disorders.
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•
Adult stem cells
Research is also carried out on mouse adult stem cells. While many scientists had assumed that these cells
were programmed to produce specific tissues and were thus no longer able to produce other sorts of tissue,
recent studies suggest that adult stem cells may be able to show more malleability than previously
believed. For instance, it has been shown that mouse neural stem cells could give rise, in specific conditions
of culture, to cells of other organs such as blood, muscle, intestine, liver and heart. Moreover marrow stromal
cells can generate astrocytes, a non-neuronal type of cell of the central nervous system and haematopoietic
stem cells can give rise to myocytes.
1.7.
First grafts of human foetal cells
Stem cells in tissues such as skin or blood are able to repair the tissues throughout life. By contrast, the nervous
system has a very limited capacity for self-repair because the neural stem cells in the adult brain are few in
number and have a poor capacity to generate new neurons for instance to repair injury.
Based on the positive results of experimentation on rodents and primates, clinical trials in patients with
Parkinson's disease have been performed on around 200 patients over the last 10 years especially in
Sweden and the USA. They have shown that the transplantation of neural cells derived from the human foetus
can have a therapeutic effect, with an important reduction of the symptoms of the disease in the treated patients.
The clinical improvement among these patients has been observed for 6-24 months after transplantation and in
some cases for 5-10 years. It has recently been shown that 10 years after the transplantation surgery, the
transplanted neural cells were still alive and producing dopamine, the compound which is deficient in the brain of
patients with Parkinson's disease.
However, this therapeutic approach still remains experimental. In addition, the availability of neural foetal
tissue is very limited. Five to six aborted foetuses are needed to provide enough neural tissue to treat one
Parkinson's patient. That is why new sources of neural cells have been explored in some countries such as the
US and Sweden. The aim is to derive neural stem cells from foetuses: these stem cells could be induced to
proliferate in culture, providing much greater amounts of neural tissue for transplantation.
1.8.
Transplantation of human haematopoietic stem cells
The transplantation of human haematopoietic stem cells is routinely used to restore the production of blood cells
in patients affected by leukaemia or aplastic anaemia after chemotherapy. There are two sources of
haematopoietic stem cells:
•
Adult stem cells: they can be retrieved under anaesthesia, from the bone marrow of donors, or from the
patients themselves (before chemotherapy). Haematopoietic stem cells can also be retrieved directly from
the blood, which requires a treatment to induce the passage of stem cells from the bone marrow into the
blood circulation.
•
Stem cells of foetal origin: haematopoietic stem cells can be retrieved from the umbilical cord blood at
birth, though care must be taken to ensure that the baby receives enough cord blood. There are at present
cord blood banks designated to facilitate haematopoietic stem cell transplantation. The systematic retrieval
and cryopreservation of cord blood, at birth, has even been considered in order to have autologous stem
cells available in case of later need. Stem cells of foetal origin give rise to less rejection reaction than adult
stem cells.
74
1.9.
Discoveries on human stem cells
In the late 70's, the progress of infertility treatment led to the birth of the first child by in vitro fertilisation. The
formation of human embryos in vitro during the course of infertility treatment has made possible the study of
human embryogenesis following fertilisation, and thus has increased our knowledge of the behaviour and
characteristics of embryonic cells at a very early stage.
Since 1998, derivation and culture of embryonic and foetal human pluripotent stem cells has been
performed, a process which had never been achieved before with human cells. A team at the University of
Wisconsin in Madison (USA) announced in November 1998 that it had successfully isolated and cultured for
several months cells from 14 human blastocysts obtained from donated surplus embryos produced by in vitro
fertilisation. This team established five embryonic ES cell lines with the ability to be grown continuously without
losing their capacity to differentiate into the many kinds of cells that constitute the body. At the same time, a team
at the Johns Hopkins University in Baltimore (USA) reported that foetal primordial germ cells had been isolated
from the gonads of foetuses obtained after pregnancy termination and cultured to make EG cells. Cell lines
derived from these cells were grown for many months while maintaining the same capacity to differentiate as the
ES cell lines.
In 1999, research on adult stem cells revealed that their plasticity was much higher than previously thought.
Adult neural stem cells have been reported to give rise occasionally to other cell types including blood cells. A
team at the University of Minnesota in Minneapolis, (USA) has shown that cells isolated from the bone marrow
of adults or children were able to become neural or muscle cells. Nevertheless, bone marrow cells with such
extraordinary malleability are extremely rare. In any case, these recent findings still require to be substantiated.
The future challenge is to control the differentiation of human stem cells. It has been shown in animals that
by culturing stem cells in the presence of certain chemical substances referred to as "growth factors", it is
possible to induce differentiation of specific cell types. Experiments on human stem cells are less advanced but
finding ways to direct differentiation is presently an active focus of research.
1.10.
What is the main interest of stem cell research and what are the hopes?
The main interests at present include:
•
Basic developmental biology. Culturing of human stem cells offers insights that cannot be studied directly
in the human embryo or understood through the use of animal models. For instance, basic research on stem
cells could help to understand the causes of birth defects, infertility and pregnancy loss. It could also be
useful to give a better understanding of normal and abnormal human development.
•
Studies of human diseases on animal models. For example, mouse ES cells can be engineered to
incorporate human mutated genes known to be associated with particular diseases and then used to make
transgenic mouse strains. If such mice express the pathology of the human disease, this confirms the
hypothesis that the gene is involved with the etiology of the disease. This strategy also yields an animal
model of the human disease which has in most cases a much better predictability for the human situation
than more conventional animal models. One of the most illustrative examples of that method is its use in
order to address the potential causes of Alzheimer's disease.
•
Culturing specific differentiated cell lines to be used for pharmacology studies and toxicology
testing. This is the most likely immediate biomedical application, making possible the rapid screening of
large numbers of chemicals. By measuring how pure populations of specific differentiated cells respond to
potential drugs, it will be possible to sort out medicinal products that may be either useful or on the contrary
problematic in human medicine.
75
•
Use of stem cells in gene therapy. Stem cells could be used as vectors for the delivery of gene therapy.
One current application in clinical trials is the use of haematopoietic stem cells genetically modified to make
them resistant to the HIV (virus responsible for AIDS).
•
Production of specific cell lines for therapeutic transplantation. If feasible, this would be the most
promising therapeutic application of ES cells. Research is being actively pursued, mostly in the mouse,
with the aim of directing the differentiation of pluripotent stem cells to produce pure populations of particular
cell types to be used for the repair of diseased or damaged tissues. For instance, the aim would be to
produce cardiac muscle cells to be used to alleviate ischaemic heart disease, pancreatic islet cells for
treatment of diabetes (juvenile onset diabetes mellitus), liver cells for hepatitis, neural cells for degenerative
brain diseases such as Parkinson's disease, and perhaps even cells for treating some forms of cancer. The
transplantation of stem cells could also help, for example, to repair spinal cord damage which occurs
frequently, mainly following trauma (for instance car accidents) and is responsible for paraplegia. Results of
that kind of cell therapy on animals are promising, but are still years away from clinical application. Even
more remote (possibly decades away) is the prospect of being able to grow whole organs in vitro, but if
tissues for the repair of organs become available, it would greatly relieve the existing unsatisfied demand for
donated organs for transplantation. In providing a potentially unlimited source of specific clinically important
cells such as bone, muscle, liver or blood cells, the use of human stem cells could open the way to a new
"regenerative medicine".
1.11.
Why is somatic cell nuclear transfer (SCNT) considered?
Apart from its interest for basic research, SCNT is considered as a possible strategy, in "regenerative medicine",
for the avoidance of immunological problems after transplantation. Neural tissues can sometimes be
transplanted from one individual to another without suffering immunological rejection, but for all other tissues,
stem cell therapy would need to be accompanied by long-term treatments with immunosuppressive drugs,
leading to increased susceptibility to infections and even to cancer.
•
One approach to avoid this immune rejection problem would involve genetic engineering of stem cells to
render them non-antigenic, or immunological manipulation of the patients to render them tolerant.
•
An alternative approach is based on somatic cell nuclear transfer. It consists of transferring nuclei from the
patient's own body cells into donated human or even animal unfertilised eggs from which the nuclei have
been removed. If these reconstructed eggs were stimulated for example with electricity to develop to the
blastocyst stage, pluripotent stem cells could be derived from them to form cells genetically identical to the
patient. No rejection of any transplanted cells would then occur.
•
Related technology could lead to the cloning of human individuals if the reconstructed embryos were
transferred to a woman’s uterus. However, this is contrary to European Community law and prohibited in
most European countries.
1.12.
Possible origins of the embryos in countries which allow embryo research
These embryos are:
•
either «spare embryos» (i.e. supernumerary embryos) created for infertility treatment to enhance
the success rate of IVF, but no longer needed for this purpose. They are intended to be discarded
but, instead, may be donated for research by the couples concerned,
•
or research embryos, created for the sole purpose of research.
76
- These may either be produced with donated gametes, i.e. they are derived from the
fertilisation in vitro of a human oocyte by a human sperm,
- or they may be produced by embryo splitting or nuclear transfer. In the latter case
they would be derived by introducing the nucleus of an adult somatic cell into an
enucleated human oocyte (sometimes misleadingly termed “embryo cloning” or
“therapeutic cloning”).
LEGAL BACKGROUND
1.13.
Legal situation in the Member States
At national level, stem cell research is not regulated as such.
With regard to embryonic stem cell research, it is thus necessary to refer to the general legislation on
embryo research. In this respect, the situation in the Member States is diverse:
- Ireland is the only country of the EU whose Constitution affirms the right to life of the “unborn” and that
this right is equal to that of the mother.
- In some Member States no legislation on embryo research exists. This is the case of Belgium and of
the Netherlands, where embryo research is nevertheless carried out. In Portugal however, in the
absence of legislation, no embryo research seems to be performed. This also seems to be the case in
Italy although artificial reproductive techniques are widely practised.
- Where embryo research is legislated, legislation either prohibits any kind of embryo research (Austria,
Germany), or authorises this research under specified conditions (Finland, Spain, Sweden, and UK). In
France, where embryo research is still prohibited, the law authorises “the study of embryos without
prejudicing their integrity” as well as preimplantation diagnosis.
- In some countries the Constitutional Courts have dealt with the use of human embryos (judgement of
the French Constitutional Court of July 27, 1994 on Bioethics, and judgement of the Spanish
Constitutional Court of July 10, 1999 on the legislation concerning assisted human reproduction
techniques).
The legal situation of many countries in Europe is under development. New legislation is being drafted
mainly in response to the challenge of stem cell research.
- In some countries, draft legislation is being prepared to allow research on stem cells derived from
supernumerary embryos after in vitro fertilisation (The Netherlands).
- In other countries, draft legislation provides for the possibility of creating embryos by nuclear transfer,
for the sole purpose of stem cell research. This is the case in Belgium, and in the UK. (In the latter case,
legislation allowed creation of embryos for the purpose of research, but only in relation to the treatment
of infertility, to contraception or to the avoidance of genetic disease). In France legislation is under
preparation.
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1.14. European legislation in the field
At the Council of Europe’s level, the Convention on Human Rights and Biomedicine signed in Oviedo in 1997
in its Article 18 establishes that it is up to each country to decide whether to authorise or not embryo research.
Each country is only obliged to respect two conditions: “to ensure adequate protection of the embryo”, that is to
say to adopt a legislation fixing the conditions and limits of such research; and to prohibit “the creation of human
embryos for research purposes”. The Convention is binding only for the States which have ratified it. In the
European Union so far only three countries have completed the procedure and some are in the process of doing
so.
At EU level, although there is no legislative competence to regulate research, some Directives allude to
the issue of embryo research and use. For instance, the Directive 98/44/EC on the legal protection of
biotechnological inventions (patenting on life) stipulates that “processes for cloning human beings” and “uses of
human embryos for industrial or commercial purposes”… “shall be considered unpatentable”. The Directive
98/79/EC on in vitro diagnostic medical devices (including the use of human tissues) provides that “ the removal,
collection and use of tissues, cells and substances of human origin shall be governed, in relation to ethics, by the
principles laid down in the Convention of the Council of Europe for the protection of human rights and dignity of
the human being with regard to the application of biology and medicine and by any Member States regulations on
this matter”.
At this same level, the Charter on Fundamental rights of the European Union approved by the European
Council in Biarritz (France) on October 14, 2000 prohibits different kinds of practices possibly related to
embryo research, namely “eugenic practices, in particular those aiming at the selection of persons ” and “the
reproductive cloning of human beings”.
1.15. US approach related to embryo research and stem cell research
The situation in the US contrasts with that in Europe. A substantial difference is a sharp distinction
between the public and the private sector. Since 1995 the US Congress has been adopting each year a
provision in the Appropriation Bill to prohibit public funding for embryo research. Thus, the National Institutes of
Health (NIH) cannot carry out embryo research, which, in the absence of legislation, remains free and beyond
control in the private sector.
New discoveries concerning the culturing of human stem cells in 1998 have led to the reopening of the debate.
The National Bioethics Advisory Committee (NBAC) issued a report on September 1999; hearings took place in
1999 and 2000 before the competent Committees of the US Congress and finally the Clinton administration
proposed that, under certain conditions, the funding of research to derive and study human ES cells be permitted.
New guidelines of the NIH were published in August 2000 according to which research on human ES cells can be
publicly funded if two conditions are respected. First, the cells must be taken from frozen spare embryos from
fertility clinics and already destined to be discarded; second, Federal funds could not be used to destroy the
embryos to obtain the cells; privately funded researchers will have to pass them on to Federally supported
scientists.
78
ETHICAL BACKGROUND
1.16.
Main ethical issues with regard to stem cell research
Human stem cell research is an example of bioethical value conflicts. On the one hand, the
prospect of new therapies, even in the far future, is attractive in offering an alternative to organ and
tissue donation. On the other hand, when this research involves the use of human embryos, it raises the
question of its ethical acceptability and of the limits and conditions for such research. Embryo research
has been extensively debated in the context of research carried out to improve IVF as a treatment for
infertility. Embryonic stem cell research raises the following specific additional ethical questions:
New types of research to be performed on human embryos. Up until now, research that involved
destroying embryos, if allowed, was limited to research on reproduction, contraception or congenital
diseases. With human stem cell research, a much wider scope of research is being considered.
The use of ES cells and stem cell lines for therapeutic purposes. Human embryos used for research
were destroyed after the research was completed and therefore were never used for fertility treatment.
What remained was additional knowledge. Human embryonic stem cell research is aimed at creating
cell lines with appropriate characteristics, in terms of purity and specificity. There is thus continuity from
the embryonic cells to the therapeutic material obtained by culture.
The creation of embryos for research purposes. This delicate issue is now raised again since there is
a scientific justification of this practice, namely the possibility of producing stem cells identical to the
patient's cells and thus avoiding problems of rejection in the context of the future “regenerative
medicine”. At the same time, creating human embryos raises new ethical concerns. The ethical
acceptability of stem cell research depends not only on the objectives but also on the source of the stem
cells; each source raising partly different ethical questions. Those who condemn embryo research in
general will not accept this difference, but for those who accept it, this issue is of major importance.
1.17.
Ethical issues in transplantation of stem cells
Clinical research and potential future applications in this field raise the same ethical issues as those dealt
with in the EGE's Opinion on Human Tissue Banking (21/07/1998), concerning the respect of the donor,
who should give informed consent to this use of the donated cells, the respect of the autonomy of the
patients, their right to safety and to the protection of their private life and the right to a fair and equal
access to new therapies.
79
2OPINION
The Group submits the following Opinion:
SCOPE OF THE OPINION
2.1
Ethical issues of stem cell research and use for clinical purposes.
This Opinion reviews ethical issues raised by human stem cell research and use, in the context of the European
Union research policy and European Community public health competence to improve human health and to set
high standards for the safety of substances of human origin.
With regard to the specific ethical questions related to the patenting of inventions involving human stem cells, on
which President Prodi requested an Opinion from the Group on 18 October 2000, this will be made public in
Brussels at a later date. The following Opinion therefore excludes the patenting issue.
GENERAL APPROACH
2.2.
Fundamental ethical principles at stake
The fundamental ethical principles applicable are those already recognised in former opinions of the EGE, and
more specifically:
- the principle of respect for human dignity
- the principle of individual autonomy (entailing the giving of informed consent, and respect for privacy
and confidentiality of personal data)
- the principle of justice and of beneficence (namely with regard to the improvement and protection of
health)
- the principle of freedom of research (which is to be balanced against other fundamental principles)
- the principle of proportionality (including that research methods are necessary to the aims pursued
and that no alternative more acceptable methods are available).
In addition, the Group considers it important to take into account, based on a precautionary approach, the
potential long-term consequences of stem cell research and use for individuals and the society.
2.3.
Pluralism and European ethics
Pluralism is characteristic of the European Union, mirroring the richness of its tradition and adding a need for
mutual respect and tolerance. Respect for different philosophical, moral or legal approaches and for diverse
cultures is implicit in the ethical dimension of building a democratic European society.
From a legal point of view, respect for pluralism is in line with Article 22 of the Charter on Fundamental Rights
on “Cultural, religious and linguistic diversity” and with Article 6 of the Amsterdam Treaty which ensures the
protection of fundamental rights at EU level, notably based on international instruments as well as common
constitutional traditions, while also stressing the respect for the national identity of all Member States.
BASIC RESEARCH ON HUMAN STEM CELLS
2.4.
Principal requirements according to the diverse sources of stem cells.
• The retrieval of adult stem cells requires the same conditions as those required in the case of
tissue donation, based on respect for the integrity of the human body and the free and informed
consent of the donor.
• The retrieval of stem cells from the umbilical cord blood after delivery requires that the donor
(the woman or the couple concerned) is informed of possible uses of the cells for this specific
purpose of research and that the consent of the donor is obtained.
• The retrieval of foetal tissues to derive stem cells requires, besides informed consent, that no
abortion is induced for the purpose of obtaining the tissues and that the termination timing and the
way it is carried out are not influenced by this retrieval.
• The derivation of stem cells from embryonic blastocysts raises the issue of the moral status of the
human embryo. In the context of European pluralism, it is up to each Member State to forbid or
authorise embryo research. In the latter case, respect for human dignity requires regulation of
80
embryo research and the provision of guarantees against risks of arbitrary experimentation and
instrumentalisation of human embryos.
2.5.
Ethical acceptability of the field of the research concerned.
The Group notes that in some countries embryo research is forbidden. But when this research is allowed, with the
purpose of improving treatment for infertility, it is hard to see any specific argument which would prohibit
extending the scope of such research in order to develop new treatments to cure severe diseases or injuries.
As in the case of research on infertility, stem cell research aims to alleviate severe human suffering. In any case,
the embryos that have been used for research are required to be destroyed. Consequently, there is no argument
for excluding funding of this kind of research from the Framework Programme of research of the European Union
if it complies with ethical and legal requirements as defined in this programme.
2.6.
Public control of ES cell research.
The Group deems it essential to underline the sensitivity attached to the use of embryonic stem cells, since this
use may change our vision of the respect due to the human embryo.
According to the Group, it is crucial to place ES cell research, in the countries where it is permitted, under strict
public control by a centralised authority - following, for instance, the pattern of the UK licensing body (the
Human Fertilisation and Embryology Authority) - and to provide that authorisations given to such research are
highly selective and based on a case by case approach, while ensuring maximum transparency. This must apply
whether the research in question is carried out by either the public or the private sector.
2.7.
Alternative methods to the creation of embryos for the purpose of stem cell research.
The Group considers that the creation of embryos for the sole purpose of research raises serious
concerns since it represents a further step in the instrumentalisation of human life.
•
The Group deems the creation of embryos with gametes donated for the purpose of stem cell
procurement ethically unacceptable, when spare embryos represent a ready alternative source.
•
The Group takes into account interest in performing somatic cell nuclear transfer (SCNT) with the
objective of studying the conditions necessary for "reprogramming" adult human cells. It is also aware
that, in view of future cell therapy, the creation of embryos by this technique may be the most
effective way to derive pluripotent stem cells genetically identical to the patient and consequently to
obtain perfectly histocompatible tissues, with the aim of avoiding rejection after transplantation. But,
these remote therapeutic perspectives must be balanced against considerations related to the
risks of trivialising the use of embryos and exerting pressure on women, as sources of oocytes,
and increasing the possibility of their instrumentalisation. Given current high levels of inefficiency in
SCNT, the provision of cell lines would require large numbers of oocytes.
•
In the opinion of the Group, in such a highly sensitive matter, the proportionality principle and a
precautionary approach must be applied: it is not sufficient to consider the legitimacy of the pursued
aim of alleviating human sufferings, it is also essential to consider the means employed. In particular, the
hopes of regenerative medicine are still very speculative and debated among scientists. Calling for
prudence, the Group considers that, at present, the creation of embryos by somatic cell nuclear
transfer for research on stem cell therapy would be premature, since there is a wide field of research
to be carried out with alternative sources of human stem cells (from spare embryos, foetal tissues and
adult stem cells).
2.8.
Stem cell research in the European Framework Programme of research
Stem cell research based on alternative sources (spare embryos, foetal tissues and adult stem cells) requires a
specific Community research budget. In particular, EU funding should be devoted to testing the validity
81
of recent discoveries about the potential of differentiation of adult stem cells. The EU should insist that the
results of such research be widely disseminated and not hidden for reasons of commercial interest.
At European Union level, within the Framework Programme of research, there is a specific responsibility to
provide funding for stem cell research. This implies the establishment of appropriate procedures and provision
of sufficient means to permit ethical assessment not only before the launching of a project but also in monitoring
its implementation.
2.9.
Stem cell research and rights of women
Women who undergo infertility treatment are subject to high psychological and physical strain. The Group
stresses the necessity to ensure that the demand for spare embryos and oocyte donation does not
increase the burden on women.
CLINICAL RESEARCH ON HUMAN STEM CELLS
The speed with which researchers, throughout the world, are moving to test stem cells in patients is remarkable,
even if ES cell transplantation is unlikely to be attempted in the near future. Clinical trials with stem cells other
than ES carried out on patients suffering from severe conditions such as Parkinson’s disease, heart disease or
diabetes raise the following issues:
2.10.
Free and informed consent
Free and informed consent is required not only from the donor but also from the recipient as stated in the Group's
opinion on Human Tissue Banking (21/07/1998). In each case, it is necessary to inform the donor (the woman or
the couple) of the possible use of the embryonal cells for the specific purpose in question before requesting
consent.
2.11. Risk-benefit assessment
Risk-benefit assessment is crucial in stem cell research, as in any research, but is more difficult as the
uncertainties are considerable given the gaps in our knowledge. Attempts to minimise the risks and increase the
benefits should include optimising the strategies for safety. It is not enough to test the cultured stem cells or
tissues derived from them for bacteria, viruses or toxicity. Safety and security aspects are of utmost importance in
the transplantation of genetically modified cells and when stem cells are derived from somatic cells. For example,
the risks that transplanted stem cells cause abnormalities or induce creation of tumours or cancer have to be
assessed. It is important that the potential benefits for the patients should be taken into account but not
exaggerated. The grounds of a precautionary approach need to be taken into account.
2.12.
Protection of the health of persons involved in clinical trials
The possibility that irreversible and potentially harmful changes are introduced in clinical applications of stem cell
research should be minimised. Techniques enhancing the possibilities of reversibility should be used whenever
possible. If, for example, genetically modified cells were encapsulated when they are transplanted in order to
stimulate neural cell growth, it should be possible for the procedure to be reversed if something goes wrong.
2.13.
Scientific evaluation of stem cell use for therapeutic purposes
It is urgent to outline strategies and specific requirements for the best evaluation of ethically sound and safe use
of stem cells as means of therapy (gene therapy, transplantation, etc.). Such an evaluation should be done in
collaboration with the European Agency for the Evaluation of Medicinal Products.
2.14.
Anonymity of the donation
Steps must be taken to protect and preserve the identity of both the donor and the recipient in stem cell research
and use. As stated in the EGE's Opinion on Human Tissue Banking (21/07/1998): "in the interests of anonymity, it
82
is prohibited to disclose information that could identify the donor, and the recipient. In general, the donor should
not know the identity of the recipient, nor should the recipient know the identity of the donor".
2.15.
Stem cell banks and safety
Procurement and storage of stem cells in stem cell banks leads to the collection and storage of a growing number
of personal and familial data. Cell banks should be regulated at European level in order to facilitate the
implementation of a precautionary approach. If unsatisfactory side effects occur, it should be possible to trace
donor and recipient and to reach their medical files. Traceability must be one of the conditions required for the
authorisation of cell banks at national or European level.
2.16.
Stem cell banks and confidentiality
In order to reconcile the traceability requirement and the need to protect the donor’s rights - medical confidentiality
and privacy - cell banks must take the necessary steps to protect confidentiality of the data.
2.17.
Prohibition of commerce in embryos and cadaveric foetal tissue
The potential for coercive pressure should not be underestimated when there are financial incentives. Embryos as
well as cadaveric foetal tissue must not be bought or sold, and not even offered for sale. Measures should be
taken to prevent such commercialisation.
2.18.
Export and import of stem cell products
Stem cell imports or exports should be licensed by public authorities either at national or European level.
Authorisation should be subject to ethical as well as safety rules.
2.19.
Education and dialogue
There is a need for continuing dialogue and education to promote the participation of citizens, including patients,
in scientific governance, namely in the social choices created by new scientific developments.
The European Group on Ethics in Science and New Technologies:
The Members
Paula Martinho da Silva
Anne McLaren
Marja Sorsa
Ina Wagner
Goran Hermerén
Gilbert Hottois
Dietmar Mieth
Octavi Quintana Trias
Stefano Rodota
Egbert Schroten
Peter Whittaker
The Chairperson
Noëlle Lenoir
83
ANNEX F: Statement for the minutes of the Council meeting 30
September 2002
ANNEX F: STATEMENT FOR THE MINUTES OF THE COUNCIL
MEETING 30 SEPTEMBER 2002
84
COUNCIL OF
Brussels, 21 October 2002 (24.10)
(OR. fr)
THE EUROPEAN UNION
12523/02
ADD 1 REV 1
LIMITE
PV/CONS 48
M I 186
IND 65
RECH 150
Subject:
ADDENDUM TO DRAFT MINUTES
2451st meeting of the COUNCIL OF THE EUROPEAN UNION
(COMPETITIVENESS) (Internal Market, Industry and Research)
held in Brussels on 30 September 2002
1
The information from the Council minutes which is contained in this addendum is
not confidential and may therefore be released to the public.
85
1
CONTENTS
Page
"A" ITEMS
Item 5.
Directive of the European Parliament and of the Council on insurance
mediation........……………………………………………………………………..3
"B" ITEMS
Item 3 (a) Council Decision adopting a specific programme for research, technological
development and demonstration: "Integrating and strengthening the European
Research Area" (20022006)...........................................................………………….................................4
Item 3 (b) Council Decision adopting a specific programme for research, technological
development and demonstration: "Structuring the European Research
Area" (2002-2006).....................................................................….........................4
Item 3 (c) Council Decision adopting a specific programme of research, technological
development and demonstration to be carried out by means of direct actions by
the Joint Research Centre (2002-2006)………………………..…………………..4
Item 3 (d) Council Decision adopting a specific programme (Euratom) for research and
training on nuclear energy (2002-2006)…………………………….……….…….4
Item 3 (e) Council Decision adopting a specific programme for research and training to be
carried out by the Joint Research Centre by means of direct actions for the
European Atomic Energy Community (20022006)...................................................…………………………………………….5
o
o
o
86
Items on the agenda concerning the definitive adoption of Council acts released to the
public
"A" items: (list: 12355/2/02 REV 2 PTS A 45)
When definitively adopting the "A" items concerning legislative acts, the Council agreed to
enter the following in the minutes:
Item 5.
Directive of the European Parliament and of the Council on insurance
mediation
PE-CONS 3639/02 SURE 34 CODEC 834
+ COR 1 (de,en,el,pt,sv)
The Council approved the European Parliament's amendments to the common
position. The abovementioned Directive is therefore deemed to have been
adopted in the form of the common position thus amended. (Legal basis: Article
47(2) and Article 55 of the Treaty establishing the European Community).
1.
Joint statement by the Council and Commission
re Article 1(3), subparagraph 2
"The Council and the Commission declare that Article 1(3), subparagraph 2 aims
to specify that, according to Community law, a Member State which permits
third-country insurance and reinsurance intermediaries to carry on their activities
in its territory from outside the Community may not provide for a regime which
results in more favourable treatment for those intermediaries than that accorded to
Community insurance and reinsurance intermediaries carrying on their activities
in its territory under the freedom of establishment and the free provision of
services in accordance with this Directive."
87
"B" items (Agenda: 12252/01 OJ CONS 49 MI 179 IND 61 RECH 148)
Item 3 (a) Council Decision adopting a specific programme for research, technological
development and demonstration: "Integrating and strengthening the
European Research Area" (2002-2006)
11385/02 RECH 139
The Council adopted the abovementioned Decision, with the Italian delegation
voting against. (Legal basis: Article 166 of the Treaty establishing the European
Community).
Item 3 (b) Council Decision adopting a specific programme for research, technological
development and demonstration: "Structuring the European Research
Area" (2002-2006)
11386/02 RECH 140
The Council adopted the abovementioned Decision (Legal basis: Article 166 of
the Treaty establishing the European Community).
Item 3 (c) Council Decision adopting a specific programme of research, technological
development and demonstration to be carried out by means of direct actions
by the Joint Research Centre (2002-2006)
11384/02 RECH 138
The Council adopted the abovementioned Decision (Legal basis: Article 166(4) of
the Treaty establishing the European Community).
Item 3 (d) Council Decision adopting a specific programme (Euratom) for research and
training on nuclear energy (2002-2006)
11382/01 RECH 136 ATO 103
+ COR 1 (nl,en,sv)
The Council adopted the abovementioned Decision (Legal basis: Article 7(1) of
the Treaty establishing the European Atomic Energy Community).
88
Item 3 (e) Council Decision adopting a specific programme for research and training to
be carried out by the Joint Research Centre by means of direct actions for
the European Atomic Energy Community (2002-2006)
11383/02 RECH 137 ATO 104
The Council adopted the abovementioned Decision (Legal basis: Article 7(1) of
the Treaty establishing the European Atomic Energy Community).
STATEMENTS
2.
Specific programmes "Integrating and strengthening the European Research
Area" and "Structuring the European Research Area"
Re:
Programme management
(a)
The Council and the Commission state that:
The programme committee of each Specific Programme will meet in different configurations
according to the nature of issues on the agenda to be discussed.
Regardless of configuration, the committee will always have the competencies of the
programme committee as defined in Article 7 of the relevant specific programme decision.
The Commission services will ensure efficiency in the committees' overall work and specific
support according to the configuration and agenda of each committee meeting. They will
ensure that the agenda of each committee meeting in any configuration will be established in
such a way and sufficiently far in advance as to enable Member States' delegations to identify
the appropriate representatives for all issues on the agenda of the meeting, and to ensure the
presence of appropriate specific expertise taking into account the characteristics of the
specific areas involved and covering, as required, in particular:
(i)
for the Specific Programme "Integrating and Strengthening the European
Research Area":
-
Life sciences, genomics and biotechnology for health;
-
Information society technologies;
-
Nanotechnologies and nanosciences, knowledge-based
multifunctional materials and new production processes and devices;
-
Aeronautics and space;
-
Food quality and safety;
89
(ii)
-
Sustainable development, global change and ecosystems;
-
Citizens and governance in a knowledge-based society;
for the Specific Programme "Structuring the European Research Area":
-
Research and innovation;
-
Human resources and mobility;
-
Research infrastructures;
-
Science and society.
In this context, the agenda of a given meeting should not call upon the specific expertise of
more than one of the above themes.
The programme committee for each specific programme will address horizontal draft
measures concerning the programme as a whole, including those issues related to overall
strategy and coherence.
For the specific programme "integrating and strengthening the European Research Area" the
committee will also address all horizontal draft measures under the heading "Specific
activities covering a wider field of research", as well as the particular draft measures related to
"Research in support of policies and anticipating scientific and technological needs",
"Horizontal research activities involving SMEs", "Specific measures in support of
international cooperation", and the part on "Strengthening the foundations of the European
Research Area", bearing in mind the need to ensure the presence of appropriate specific
expertise where relevant.
In the more specific configurations the committee of each programme will address the
relevant part of the work programmes and their periodic reviews, including the use of
implementation instruments, any subsequent adjustment to their use, the content of the calls
for proposals as well as the draft implementing measures concerning the approval of funding
of RTD actions within the relevant field.
As for themes encompassing more than one domain, the agenda should be defined in such a
way as to ensure, whenever appropriate, both the overall coherence as well as the more
specific articulation of themes and expertise. This should apply in particular where calls for
proposals and project funding are on the agenda.
The reimbursement of one representative and one expert/adviser, from each Member State,
participating in programme committee meetings will be effected from the budget of each
respective specific programme in full respect of its budgetary envelope. The reimbursement
of the second person (expert/adviser) will not constitute a precedent for committees operating
in other fields of Community policy.
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(b)
The Commission states that:
In order to ensure efficiency and transparency of implementation, it will systematically make
available to the Programme Committee comprehensive information covering all the proposals
received for RTD actions as well as those eventually funded, regardless of their size.
The Commission will provide the information in a user-friendly form, including whenever
possible in electronic form, in time for the Committee to take due account of it, at least two
weeks in advance for matters for the committee's opinion and one week for matters for
information.
In addition to information periodically made public through the Annual Report under Article
173 of the Treaty, as well as through the monitoring and the 5-year assessment reports, data
for each priority or area will be made available during the last quarter of each year that will
encompass, in a consolidated presentation, the information regularly supplied to committees
on programme implementation and budget execution.
This information will cover all stages, from calls for proposals, through the evaluation of
proposed RTD actions, their selection, as well as the signature of contracts and their
subsequent implementation.
It will in particular include an overview of each call and for each proposal:
– summary information;
– the evaluation panels' ranking and summary reports; and
–
the Commission's intentions as to proposals to be rejected or to be retained
for negotiation;
– total budget and requested Community contribution.
The Commission will provide information regularly, and at least annually, on:
–
the contracts signed (including partners, areas, content, resources and
Member States' participation) and on their major developments, together
with
– overviews of programme progress and implementation achievements, as well
as
–
the lists of persons having acted as evaluators over the previous period once
all decisions have been made on the relevant call.
3.
Specific programme "Integrating and strengthening the European Research
Area"
Re:
Article 3, application of ethical principles
The Council and the Commission agree that detailed implementing provisions concerning
research activities involving the use of human embryos and human embryonic stem cells
91
which may be funded under the 6th Framework Programme shall be established by 31
December 2003. The Commission states that, during that period and pending establishment
of the detailed implementing provisions, it will not propose to fund such research, with the
exception of the study of banked or isolated human embryonic stem cells in culture. The
Commission will monitor the scientific advances and needs as well as the evolution of
international and national legislation, regulations and ethical rules regarding this issue, taking
into account also the opinions of the European Group of Advisers on the Ethical Implications
of Biotechnology (1991–1997) and the opinions of the European Group on Ethics in Science
and New Technologies (as from 1998), and report to the European Parliament and the Council
by September 2003.
The Council states that it intends to discuss this issue at a meeting in September 2003.
In the review of any subsequent proposal submitted to Council when applying Article 5 of
Decision 1999/468/EC, the Commission recalls its statement concerning Article 5 of
Decision 1999/468/EC, according to which the Commission, in order to find a balanced
solution, will act in such a way as to avoid going against any predominant position which
might emerge within the Council against the appropriateness of an implementing measure (cf.
OJ C 203, 17.7.1999, p. 1).
The Council notes the intention of the Commission to submit to the Programme Committee,
established under the specific research programme "Integrating and strengthening the ERA",
procedural modalities concerning research involving the use of human embryos and human
embryonic stem cells, in accordance with Article 6, paragraph 3, first indent.
The Council further notes the intention of the Commission to present to Council and
Parliament in spring 2003 a report on human embryonic stem cell research which will form
the basis for discussion at an inter-institutional seminar on bioethics.
Taking into account the seminar's outcome, the Commission will submit, based on Article
166(4) of the Treaty, a proposal establishing further guidelines on principles for deciding on
the Community funding of research projects involving the use of human embryos and human
embryonic stem cells.
The Council and the Commission will do their utmost, counting on the support of the
European Parliament, to complete the legislative procedure as early as possible and at the
latest in December 2003.
The Council and the Commission expect that the abovementioned seminar will contribute, as
suggested by the European Parliament, to a Europe-wide and well-structured discussion
process on the ethical issues of modern biotechnology, particularly on human embryonic stem
cells, in order to enhance public understanding.
The Council and the Commission note that the ethical acceptability of various research fields
is related to the diversity among Member States, and is governed by national law in
accordance with the principle of subsidiarity. Moreover, the Commission notes that research
using human embryos and human embryonic stem cells is allowed in several Member States,
but not in others.
92
Re:
COST
The Council and the Commission share the view of the recent report of the COST Assessment
Panel that COST represents a long track record in cross-border cooperation and coordination
of nationally financed RTD activities which constitutes a feature of direct relevance to
building the European Research Area, while also acknowledging the scope for significant
changes to the way COST is organised. Moreover, the Council notes that the Commission
will not provide the administrative and scientific secretariat to any COST actions initiated
during the Sixth Framework Programme. It notes also that the Commission, recognising that
a new COST secretariat may not be fully operational by the end of 2002, is however prepared
to continue providing the secretariat to COST actions during a transition period of a few
months.
The Council and the Commission note that COST is in a process of being reformed and
recognise that, following a successful outcome, and given also the recent expansion of COST
and the growth in its number of Actions, a substantial grant from the Sixth Framework
Programme could be justified.
The Council welcomes the Commission's intention to become a partner of COST, with a view
to further developing synergy between the Framework Programme and COST. The Council
invites the Commission to take appropriate steps in this respect.
4.
Specific programme "Structuring the European Research Area"
Re:
Human resources and mobility
The Commission states that in the implementation of the human resources and mobility
actions under the present Specific Programme, family-related circumstances, such as
maternity or paternity leave, will be inter alia taken into account, according to national
legislations, so that potential beneficiaries will not suffer from the abovementioned
circumstances.
5.
Specific programme "Direct actions by the Joint Research Centre" (EC)
The Commission considers that, according to its mission and when requested, the JRC should
support the European Parliament in the conception and implementation process of EU
policies. Therefore the Commission welcomes the EP's intention to create an ad hoc
committee aimed at ensuring an appropriate interface with the JRC.
The Commission wishes to confirm that the JRC multiannual work programme will be
available on the JRC website: http://www.jrc.org.
93
6.
Specific programme “Nuclear Energy” (Euratom)
Re:
Voting rights at the consultative committee
The Council and the Commission acknowledge the unanimous agreement of the consultative
committee for the fusion programme (CCFP) on the following weighted voting system, which
should be applied within the Committee referred to in Article 6(2), when dealing with fusion
related aspects. Accordingly, the Commission will take the appropriate steps with a view to
amending the Council Decision of 16 December 1980 – as last amended by Council Decision
95/1/EC, Euratom, ECSC of 1 January 1995 – setting up the consultative committee for the
fusion programme.
Germany
5
Austria
2
Belgium
2
Denmark
2
Spain
3
Finland
2
France
5
Greece
2
Ireland
2
Italy
5
Luxembourg
1
Netherlands
2
Portugal
2
United Kingdom
5
Sweden
2
Switzerland
2
_____________________
Total
44
For the adoption of an opinion, the required majority is 23 votes in favour by at least eight
delegations.
94
7.
Unilateral and bilateral statements relating to the specific programmes
(a)
Statement by Germany and Austria on Article 3 of the specific programme
"Integrating and strengthening the European research area"
"Germany and Austria emphasise that they maintain their position that, even after the end of
the moratorium in December 2003, research using human embryos and human embryonic
stem cells, with the exception of stem cells already held in banks or isolated in culture, should
not be funded under the 6th Framework Programme. Moreover, Germany and Austria assume
that, under the second specific programme, "Structuring the European Research Area", the
Commission will not fund any research activities ineligible for funding on account of the
statement for the minutes concerning the first specific programme "Integrating and
strengthening the European Research Area"."
(b)
Statement by Ireland (bioethics)
"Ireland, in supporting the adoption of the specific programmes to implement the Sixth
Framework Programme for reseach, recalls its statements pertaining to research that cannot be
carried out in Ireland. Ireland also recalls the Council statement and its joint statement with
Italy, Germany, Portugal and Austria, pertaining to the further elaboration of detailed
guidelines on ethical aspects.
Ireland welcomes
(c)
–
the progress achieved to date in the elaboration of detailed implementing provisions;
–
the recognition that its laws, regulations and guidelines apply in respect of any
research carried out in Ireland;
–
the Commission statement regarding non-funding in respect of research activities on
human embryos or human embryonic stem cells under the Sixth Framework
Programme;
–
the Commission's intention to present a proposal in 2003, establishing further
guidelines on principles for deciding on Community funding of research projects
involving the use of human embryos or human embryonic stem cells. In the course
of this process, Ireland which shares a number of the concerns expressed by Italy,
Germany, Portugal and Austria, will continue to focus on the need to ensure utmost
respect for human life and the protection of human dignity;
-
the establishment of a Regulatory Committee which will consider any project
proposals for research funding in ethically sensitive areas."
Statement by Italy (bioethics and funding of ITER)
"Italy notes the Council and Commission statements on the "bioethics question" in connection
with the adoption of the Specific Programmes implementing the Sixth Framework
Programme for research 2002-2006. These statements represent significant progress in the
endeavour to reach a joint position. In this context Italy considers that only research using
95
stem-cells derived from human embryos at a date preceding today or the date of the launch of
the Sixth Framework Programme is admissible for Community funding.
With regard to the Specific Programme on Integrating and strengthening the European
Research Area, Italy must reaffirm its vote against this. In line with the views previously
expressed in the Research Council on 10 December 2001 and 3 June 2002 on respect for
human dignity and protection of human life, Italy believes that research on human embryos
directly or indirectly involving the destruction of the embryo should not be funded under the
Sixth Framework Programme.
Regarding the EURATOM Specific Programme on Nuclear Energy, Italy takes a favourable
view but points out that the funding provided for the ITER facility should not necessarily be
interpreted as an endorsement of the scientific and technological choices made in the design
of the facility. Italy believes that these choices should be given further scientific
consideration before a final decision is taken on the feasibility of the ITER programme."
(d)
Statement by Portugal (bioethics)
"Portugal congratulates the Presidency on the efforts it has made in the field of bioethics,
without which it would not have been possible to launch the Sixth Framework Programme for
research and technological development and the relevant specific programmes.
Portugal can give its agreement to the compromise reached, because it believes that
compromise recognises the importance it attaches to issues of bioethics and research as well
as the sensitivity of any future financing of research work on human embryo cells and
embryonic stem cells. Portugal points out that this is a position shared by a number of other
Member States and that it associates itself with many of the concerns which Italy has raised
within the Council.
Portugal further stresses that research, especially through the Framework Programme, plays
an important part in economic growth, employment and social cohesion, particularly in the
context of a knowledge-based society and economy."
96